Tensin Phosphotyrosine-binding (PTB) domain; Tensin is a a focal adhesion protein, which contains a C-terminal SH2 domain followed by a PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 578 GAATNVLWLYSCDTESLTGNEAIRKAIRQMYGQQPLPQPTEVHFKVSSQGITLTDNTRKKFFRKHYKADVISHCAIDPEN 657
Cdd:cd01213    1 GAACNVLYLGSVDTESLTGPQAVRKAVSETLERDPLPTPTVVHFKVSEQGITLTDNQRKLFFRRHYPLNTVSFCGMDPEN 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 281361450 658 RMWTSEGESDKKT--IFAFVARRSHSSTDNQCHVFCDLSVSQPAAAIVSFANRTLP 711
Cdd:cd01213   81 RKWQKYDLRGSKPsrIFGFVARKQGSSTENVCHLFAELDPEQPASAIVNFVNKVLL 136

Tensin Phosphotyrosine-binding (PTB) domain; Tensin is a a focal adhesion protein, which contains a C-terminal SH2 domain followed by a PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 578 GAATNVLWLYSCDTESLTGNEAIRKAIRQMYGQQPLPQPTEVHFKVSSQGITLTDNTRKKFFRKHYKADVISHCAIDPEN 657
Cdd:cd01213    1 GAACNVLYLGSVDTESLTGPQAVRKAVSETLERDPLPTPTVVHFKVSEQGITLTDNQRKLFFRRHYPLNTVSFCGMDPEN 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 281361450 658 RMWTSEGESDKKT--IFAFVARRSHSSTDNQCHVFCDLSVSQPAAAIVSFANRTLP 711
Cdd:cd01213   81 RKWQKYDLRGSKPsrIFGFVARKQGSSTENVCHLFAELDPEQPASAIVNFVNKVLL 136

Phosphotyrosine-binding domain; The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C-terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 (pfam00017) domain and a region similar to the tumour suppressor PTEN. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450  580 ATNVLWLYSCDTESLTGNEAIRKAIR--QMYGQQPLPQPTEVHFKVSSQGITLTDNTRKKFFRkHYKADVISHCAIDPEN 657
Cdd:pfam08416   1 QYRVEHLTTFELDSLTGLQAVEDAIRklQLLDAQGRVWTQEMLLQVSDQGITLTDNETKEELE-SYPLDSISHCQAVLND 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 281361450  658 RMWTSegesdkktIFAFVARRSHSSTDNQcHVFC--DLSVSQPAAAIVSFANRTLPTEKLR 716
Cdd:pfam08416  80 GRYNS--------ILALVCQEPGQSKPDV-HLFQcdELGAELIAEDIESALSDVRLGKPKK 131

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450   458 WYKPNLTREDAIALLASAQPGTFLVRDSTTYKDSYGLVVRVsqpppgsQELVRHFLIEPTKGGVhlKGCDDEPVFTSLSA 537
Cdd:smart00252   3 WYHGFISREEAEKLLKNEGDGDFLVRDSESSPGDYVLSVRV-------KGKVKHYRIRRNEDGK--FYLEGGRKFPSLVE 73

                   ..
gi 281361450   538 LV 539
Cdd:smart00252  74 LV 75

Tensin Phosphotyrosine-binding (PTB) domain; Tensin is a a focal adhesion protein, which contains a C-terminal SH2 domain followed by a PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 578 GAATNVLWLYSCDTESLTGNEAIRKAIRQMYGQQPLPQPTEVHFKVSSQGITLTDNTRKKFFRKHYKADVISHCAIDPEN 657
Cdd:cd01213    1 GAACNVLYLGSVDTESLTGPQAVRKAVSETLERDPLPTPTVVHFKVSEQGITLTDNQRKLFFRRHYPLNTVSFCGMDPEN 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 281361450 658 RMWTSEGESDKKT--IFAFVARRSHSSTDNQCHVFCDLSVSQPAAAIVSFANRTLP 711
Cdd:cd01213   81 RKWQKYDLRGSKPsrIFGFVARKQGSSTENVCHLFAELDPEQPASAIVNFVNKVLL 136

Phosphotyrosine-binding domain; The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C-terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 (pfam00017) domain and a region similar to the tumour suppressor PTEN. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450  580 ATNVLWLYSCDTESLTGNEAIRKAIR--QMYGQQPLPQPTEVHFKVSSQGITLTDNTRKKFFRkHYKADVISHCAIDPEN 657
Cdd:pfam08416   1 QYRVEHLTTFELDSLTGLQAVEDAIRklQLLDAQGRVWTQEMLLQVSDQGITLTDNETKEELE-SYPLDSISHCQAVLND 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 281361450  658 RMWTSegesdkktIFAFVARRSHSSTDNQcHVFC--DLSVSQPAAAIVSFANRTLPTEKLR 716
Cdd:pfam08416  80 GRYNS--------ILALVCQEPGQSKPDV-HLFQcdELGAELIAEDIESALSDVRLGKPKK 131

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450   577 HGAATNVLWLYSCDTESLTGNEAIRKAIRQMYGQQP--LPQPTEVHFKVSSQGITLTDNTRKKFFRkHYKADVISHCAID 654
Cdd:smart00462   2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGseKKEPQKVILSISSRGVKLIDEDTKAVLH-EHPLRRISFCAVG 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 281361450   655 PENRmwtsegesdkkTIFAFVARRSHSStDNQCHVF--CDLSVSQPAAAIVSFA 706
Cdd:smart00462  81 PDDL-----------DVFGYIARDPGSS-RFACHVFrcEKAAEDIALAIGQAFQ 122

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 582 NVLWLYSCDTESLTGNEAIRKAIRQMYGQ--QPLPQPTEVHFKVSSQGITLTDNTRKKFFRKHYKADvISHCAIDPENrm 659
Cdd:cd00934    4 QVKYLGSVEVGSSRGVDVVEEALKALAAAlkSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHR-ISYCGRDPDN-- 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 281361450 660 wtsegesdkKTIFAFVARRsHSSTDNQCHVFCDLSVSQpAAAIV 703
Cdd:cd00934   81 ---------PNVFAFIAGE-EGGSGFRCHVFQCEDEEE-AEEIL 113

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are members of the CSK-family of protein tyrosine kinases. These proteins suppress activity of Src-family kinases (SFK) by selectively phosphorylating the conserved C-terminal tail regulatory tyrosine by a similar mechanism. CHK is also capable of inhibiting SFKs by a non-catalytic mechanism that involves binding of CHK to SFKs to form stable protein complexes. The unphosphorylated form of SFKs is inhibited by CSK and CHK by a two-step mechanism. The first step involves the formation of a complex of SFKs with CSK/CHK with the SFKs in the complex are inactive. The second step, involves the phosphorylation of the C-terminal tail tyrosine of SFKs, which then dissociates and adopt an inactive conformation. The structural basis of how the phosphorylated SFKs dissociate from CSK/CHK to adopt the inactive conformation is not known. The inactive conformation of SFKs is stabilized by two intramolecular inhibitory interactions: (a) the pYT:SH2 interaction in which the phosphorylated C-terminal tail tyrosine (YT) binds to the SH2 domain, and (b) the linker:SH3 interaction of which the SH2-kinase domain linker binds to the SH3 domain. SFKs are activated by multiple mechanisms including binding of the ligands to the SH2 and SH3 domains to displace the two inhibitory intramolecular interactions, autophosphorylation, and dephosphorylation of YT. By selective phosphorylation and the non-catalytic inhibitory mechanism CSK and CHK are able to inhibit the active forms of SFKs. CSK and CHK are regulated by phosphorylation and inter-domain interactions. They both contain SH3, SH2, and kinase domains separated by the SH3-SH2 connector and SH2 kinase linker, intervening segments separating the three domains. They lack a conserved tyrosine phosphorylation site in the kinase domain and the C-terminal tail regulatory tyrosine phosphorylation site. The CSK SH2 domain is crucial for stabilizing the kinase domain in the active conformation. A disulfide bond here regulates CSK kinase activity. The subcellular localization and activity of CSK are regulated by its SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAQPGTFLVRDSTTYKDSYGLVVRVSQPppgsqelVRHFLIEPTKGGVhlkGCDDEPVFTSLSA 537
Cdd:cd09937    5 WFHGKISREEAERLLQPPEDGLFLVRESTNYPGDYTLCVSFEGK-------VEHYRVIYRNGKL---TIDEEEYFENLIQ 74

                 ....*
gi 281361450 538 LVfEH 542
Cdd:cd09937   75 LV-EH 78

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb7 is part of the Grb7 family of proteins which also includes Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 455 SQFWYKPNLTREDAIALLASAQ--PGTFLVRDSTtyKDSYGLVVRVSQpppgsQELVRHFLIEPTK--GGVHLKGCDDEP 530
Cdd:cd10413    4 TQPWFHGRISREESQRLIGQQGlvDGVFLVRESQ--RNPQGFVLSLCH-----LQKVKHYLILPSEeeGRLYFSMDDGQT 76

                         90       100
                 ....*....|....*....|....
gi 281361450 531 VFTSLSALVFEHSISQLALPCLLR 554
Cdd:cd10413   77 RFTDLLQLVEFHQLNRGILPCLLR 100

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in the hematopoietic cells, in neural tissues, liver, and adipose tissue. There are two alternatively spliced forms of Lyn. Lyn plays an inhibitory role in myeloid lineage proliferation. Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation, triggering a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phospholipase C2 (PLC2) and phosphatidyl inositol-3 kinase. These kinases play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FC RIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1 which further down modulate signaling pathways, attenuate cell activation and can mediate tolerance. Lyn also plays a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1) leading to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. It is the primary Src family member involved in signaling downstream of the B cell receptor. Lyn plays an unusual, 2-fold role in B cell receptor signaling; it is essential for initiation of signaling but is also later involved in negative regulation of the signal. Lyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 281361450 458 WYKPNLTREDA-IALLASA-QPGTFLVRDSTTYKDSYGLVVRVSQPPPGsqELVRHFLIEPTKGG 520
Cdd:cd10364    5 WFFKDITRKDAeRQLLAPGnSAGAFLIRESETLKGSYSLSVRDYDPQHG--DVIKHYKIRSLDNG 67

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ABL-family proteins are highly conserved tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. By combining this cassette with actin-binding and -bundling domain, ABL proteins are capable of connecting phosphoregulation with actin-filament reorganization. Vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain which is used to mediate DNA damage-repair functions, while ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. SH2 is involved in several autoinhibitory mechanism that constrain the enzymatic activity of the ABL-family kinases. In one mechanism SH2 and SH3 cradle the kinase domain while a cap sequence stabilizes the inactive conformation resulting in a locked inactive state. Another involves phosphatidylinositol 4,5-bisphosphate (PIP2) which binds the SH2 domain through residues normally required for phosphotyrosine binding in the linker segment between the SH2 and kinase domains. The SH2 domain contributes to ABL catalytic activity and target site specificity. It is thought that the ABL catalytic site and SH2 pocket have coevolved to recognize the same sequences. Recent work now supports a hierarchical processivity model in which the substrate target site most compatible with ABL kinase domain preferences is phosphorylated with greatest efficiency. If this site is compatible with the ABL SH2 domain specificity, it will then reposition and dock in the SH2 pocket. This mechanism also explains how ABL kinases phosphorylates poor targets on the same substrate if they are properly positioned and how relatively poor substrate proteins might be recruited to ABL through a complex with strong substrates that can also dock with the SH2 pocket. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAQPGTFLVRDSTTYKDSYGLVVRvsqpppgSQELVRHFLI-EPTKGGVHLKgcdDEPVFTSLS 536
Cdd:cd09935    5 WYHGPISRNAAEYLLSSGINGSFLVRESESSPGQYSISLR-------YDGRVYHYRIsEDSDGKVYVT---QEHRFNTLA 74

                         90       100
                 ....*....|....*....|
gi 281361450 537 ALVFEHSISQLALPCLLRLP 556
Cdd:cd09935   75 ELVHHHSKNADGLITTLRYP 94

Src homology 2 (SH2) domain found in Ras and Rab interactor (RIN)-family; The RIN (AKA Ras interaction/interference) family is composed of RIN1, RIN2 and RIN3. These proteins have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs, and RIN3 specifically functions as a Rab31-GEF. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAQPGTFLVRDSTTYKDsygLVVRVSQPPPGSQELVRHFLIEPTKGGVHLKGcddepvftslSA 537
Cdd:cd10339   12 WLQLQLNAAEAAHMLQTEPPGTFLVRKSNTRQC---QVLCMRLPEASGPAFVSEHYIKESPGGVSLEG----------SE 78

                         90       100
                 ....*....|....*....|....*
gi 281361450 538 LVFEHSISQLALPCLlrlpDRDIVP 562
Cdd:cd10339   79 LMFPDLFRLIAFYCH----SRDILP 99

Src homology 2 (SH2) domain in lymphocyte cell kinase (Lck); Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. It is expressed in the brain, T-cells, and NK cells. The unique domain of Lck mediates its interaction with two T-cell surface molecules, CD4 and CD8. It associates with their cytoplasmic tails on CD4 T helper cells and CD8 cytotoxic T cells to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck phosphorylase the intracellular chains of the CD3 and zeta-chains of the TCR complex, allowing ZAP-70 to bind them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates Linker of Activated T cells (LAT), a transmembrane protein that serves as a docking site for proteins including: Shc-Grb2-SOS, PI3K, and phospholipase C (PLC). The tyrosine phosphorylation cascade culminates in the intracellular mobilization of a calcium ions and activation of important signaling cascades within the lymphocyte, including the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-kappaB, and AP-1. These transcription factors regulate the production cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains a SH3 domain, a SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAQ--PGTFLVRDSTTYKDSYGLVVRVSQPPPGsqELVRHFLIEPT-KGGVHLKgcdDEPVFTS 534
Cdd:cd10362    5 WFFKNLSRNDAERQLLAPGntHGSFLIRESETTAGSFSLSVRDFDQNQG--EVVKHYKIRNLdNGGFYIS---PRITFPG 79

                 ....*....
gi 281361450 535 LSALVFEHS 543
Cdd:cd10362   80 LHELVRHYT 88

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAQPGTFLVRDSTTykDSYGLVVRVSqpppgSQELVRHFLIEPTKG----GVHLKGCDDEPVFT 533
Cdd:cd10388   12 WYWGPMSWEDAEKVLSNKPDGSFLVRDSSD--DRYIFSLSFR-----SQGSVHHTRIEQYQGtfslGSRNKFVDRSQSLV 84

                         90
                 ....*....|..
gi 281361450 534 SLSALVFEHSIS 545
Cdd:cd10388   85 EFIERAVEHSRS 96

Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. This cd contains the SH2 domain found in Fyn isoform a type proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDA-IALLASAQP-GTFLVRDSTTYKDSYGLVVRVSQPPPGSQelVRHFLIEP-TKGGVHLKgcdDEPVFTS 534
Cdd:cd10418    5 WYFGKLGRKDAeRQLLSFGNPrGTFLIRESETTKGAYSLSIRDWDDMKGDH--VKHYKIRKlDNGGYYIT---TRAQFET 79

                         90       100
                 ....*....|....*....|..
gi 281361450 535 LSALVFEHSISQLALPCLLRLP 556
Cdd:cd10418   80 LQQLVQHYSERAAGLCCRLVVP 101

Src homology 2 domain found in Src-like adaptor proteins; SLAP belongs to the subfamily of adapter proteins that negatively regulate cellular signaling initiated by tyrosine kinases. It has a myristylated N-terminus, SH3 and SH2 domains with high homology to Src family tyrosine kinases, and a unique C-terminal tail, which is important for c-Cbl binding. SLAP negatively regulates platelet-derived growth factor (PDGF)-induced mitogenesis in fibroblasts and regulates F-actin assembly for dorsal ruffles formation. c-Cbl mediated SLAP inhibition towards actin remodeling. Moreover, SLAP enhanced PDGF-induced c-Cbl phosphorylation by SFK. In contrast, SLAP mitogenic inhibition was not mediated by c-Cbl, but it rather involved a competitive mechanism with SFK for PDGF-receptor (PDGFR) association and mitogenic signaling. Accordingly, phosphorylation of the Src mitogenic substrates Stat3 and Shc were reduced by SLAP. Thus, we concluded that SLAP regulates PDGFR signaling by two independent mechanisms: a competitive mechanism for PDGF-induced Src mitogenic signaling and a non-competitive mechanism for dorsal ruffles formation mediated by c-Cbl. SLAP is a hematopoietic adaptor containing Src homology (SH)3 and SH2 motifs and a unique carboxy terminus. Unlike c-Src, SLAP lacks a tyrosine kinase domain. Unlike c-Src, SLAP does not impact resorptive function of mature osteoclasts but induces their early apoptosis. SLAP negatively regulates differentiation of osteoclasts and proliferation of their precursors. Conversely, SLAP decreases osteoclast death by inhibiting activation of caspase 3. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDA--IALLASAQPGTFLVRDSTTYKDSYGLVVRVSQPPpgSQELVRHFLIEP-TKGGVHLkgcddEP--VF 532
Cdd:cd10344   12 WLFEGLSREKAeeLLMLPGNQVGSFLIRESETRRGCYSLSVRHRGSQ--SRDSVKHYRIFRlDNGWFYI-----SPrlTF 84

                         90       100
                 ....*....|....*....|
gi 281361450 533 TSLSALVFEHSISQLALPCL 552
Cdd:cd10344   85 QCLEDMVNHYSESADGLCCV 104

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, SHE, SHF); SHB, SHD, SHE, and SHF are SH2 domain-containing proteins that play various roles throughout the cell. SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. SHE is expressed in heart, lung, brain, and skeletal muscle, while expression of SHD is restricted to the brain. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 456 QFWYKPNLTREDAIALLASAQPGTFLVRDSTTYKDSYGLVVRVSQ----------------------PPPGSQELVRHFL 513
Cdd:cd09945    1 QGWYHGAITRIEAESLLRPCKEGSYLVRNSESTKQDYSLSLKSAKgfmhmriqrnetgqyilgqfsrPFETIPEMIRHYC 80

                         90
                 ....*....|..
gi 281361450 514 IE--PTKGGVHL 523
Cdd:cd09945   81 LNklPVRGAEHM 92

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the CRK proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK. CRKs regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. The SH2 domain of CRK associates with tyrosine-phosphorylated receptors or components of focal adhesions, such as p130Cas and paxillin. CRK transmits signals to small G proteins through effectors that bind its SH3 domain, such as C3G, the guanine-nucleotide exchange factor (GEF) for Rap1 and R-Ras, and DOCK180, the GEF for Rac6. The binding of p130Cas to the CRK-C3G complex activates Rap1, leading to regulation of cell adhesion, and activates R-Ras, leading to JNK-mediated activation of cell proliferation, whereas the binding of CRK DOCK180 induces Rac1-mediated activation of cellular migration. The activity of the different splicing isoforms varies greatly with CRKI displaying substantial transforming activity, CRKII less so, and phosphorylated CRKII with no biological activity whatsoever. CRKII has a linker region with a phosphorylated Tyr and an additional C-terminal SH3 domain. The phosphorylated Tyr creates a binding site for its SH2 domain which disrupts the association between CRK and its SH2 target proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 281361450 452 RSSsqfWYKPNLTREDAIALLASAQPGTFLVRDSTTYKDSYGLVVR 497
Cdd:cd09926    6 RSS---WYFGPMSRQEAQELLQGQRHGVFLVRDSSTIPGDYVLSVS 48

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAQPGTFLVRDSTTYKDSYGLVVRVSqpppGSQELVRHFliepTKGGVHlkGCDDEPVFTSLSA 537
Cdd:cd09942    9 WYWGDISREEVNEKMRDTPDGTFLVRDASTMKGDYTLTLRKG----GNNKLIKIF----HRDGKY--GFSDPLTFNSVVE 78

                         90
                 ....*....|.
gi 281361450 538 LVFEHSISQLA 548
Cdd:cd09942   79 LINYYRNNSLA 89

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide variety of pathways including regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. An adapter protein, SHC has been implicated in Ras activation following the stimulation of a number of different receptors, including growth factors [insulin, epidermal growth factor (EGF), nerve growth factor, and platelet derived growth factor (PDGF)], cytokines [interleukins 2, 3, and 5], erythropoietin, and granulocyte/macrophage colony-stimulating factor, and antigens [T-cell and B-cell receptors]. SHC has been shown to bind to tyrosine-phosphorylated receptors, and receptor stimulation leads to tyrosine phosphorylation of SHC. Upon phosphorylation, SHC interacts with another adapter protein, Grb2, which binds to the Ras GTP/GDP exchange factor mSOS which leads to Ras activation. SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALLASAqpGTFLVRDSTTYKDSYGLVVRVSQPPpgsqelvRHFLIEPTKGGVHLKgcddEPVFTSLSA 537
Cdd:cd09925    9 WYHGKMSRRDAESLLQTD--GDFLVRESTTTPGQYVLTGMQNGQP-------KHLLLVDPEGVVRTK----DRVFESISH 75

                         90       100       110
                 ....*....|....*....|....*....|.
gi 281361450 538 LVFEHsiSQLALPCLLRLPDRDIVPPVRATT 568
Cdd:cd09925   76 LINYH--VTNGLPIISEGSELHLRRPVRRPA 104

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 281361450 455 SQFWYKPNLTREDAIALL-ASAQPGTFLVRDSTTYKDSYGLVVRV 498
Cdd:cd09932    3 SKEWFHANLTREQAEEMLmRVPRDGAFLVRPSETDPNSFAISFRA 47

uncharacterized protein LOC417372 Phosphotyrosine-binding (PTB) PH-like fold; The function of LOC417372 and its related proteins are unknown to date. Members here contain a N-terminal RUN domain, followed by a PDZ domain, and a C-terminal PTB domain. The RUN domain is involved in Ras-like GTPase signaling. The PDZ domain (also called DHR/Dlg homologous region or GLGF after its conserved sequence motif) binds C-terminal polypeptides, internal (non-C-terminal) polypeptides, and lipids. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 579 AATNVLWLYSCDTESLTGNEAIRKAIRQMYGQQPLPqPTEVHFKVSSQGITLTD-NTRKKFFRKHYKAdvISHCaidpen 657
Cdd:cd13168    1 ALYKALYLGQVEVGEDGGVEQIESAAIIVVLESDLT-PKEVLLELGEIGVTVWDkSTSEVLFKHSFPE--ISSC------ 71

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 281361450 658 rmwtseGE-SDKKTIFAFVARRSHSSTDNQ--CHVFCDLSVSQPAAAIVSFA---NRT 709
Cdd:cd13168   72 ------GRrVDDPNYFAYIAGDTPCSLAKHfvCYVFEAADEEEAETILQGIAqgfKRT 123

Low Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1) in mammals and similar proteins Phosphotyrosine-binding (PTB) PH-like fold; The null mutations in the LDL receptor adaptor protein 1 (LDLRAP1) gene, which serves as an adaptor for LDLR endocytosis in the liver, causes autosomal recessive hypercholesterolemia (ARH). LDLRAP1 contains a single PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd contains mammals, insects, and sponges.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 583 VLWLYSCDTESLTGNEAIRKAIRQM--------YGQQplpqptEVHFKVSSQGITLTDNTRKK------FFRkhykadvI 648
Cdd:cd13159    7 LKYLGSTLVEKPKGEGATAEAVKTIiamakasgKKLQ------KVTLTVSPKGIKVTDSATNEtilevsIYR-------I 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 281361450 649 SHCAIDPENrmwtsegesDKktIFAFVARRSHSSTdNQCHVF 690
Cdd:cd13159   74 SYCTADANH---------DK--VFAFIATNQDNEK-LECHAF 103

C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in its carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 458 WYKPNLTREDAIALL--ASAQPGTFLVRDSTTYKDSYGLVVRVSQPPPG---SQELVRHFLIeptkggvhlkgcDDEPVF 532
Cdd:cd10348    2 WLHGALDRNEAVEILkqKADADGSFLVRYSRRRPGGYVLTLVYENHVYHfeiQNRDDKWFYI------------DDGPYF 69

                         90
                 ....*....|
gi 281361450 533 TSLSALVfEH 542
Cdd:cd10348   70 ESLEHLI-EH 78

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and SLAM-associated protein (SAP); The SH2-containing inositol-5'-phosphatase, SHIP (also called SHIP1/SHIP1a), is a hematopoietic-restricted phosphatidylinositide phosphatase that translocates to the plasma membrane after extracellular stimulation and hydrolyzes the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. As a result, SHIP dampens down PIP3 mediated signaling and represses the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. PIP3 recruits lipid-binding pleckstrin homology(PH) domain-containing proteins to the inner wall of the plasma membrane and activates them. PH domain-containing downstream effectors include the survival/proliferation enhancing serine/threonine kinase, Akt (protein kinase B), the tyrosine kinase, Btk, the regulator of protein translation, S6K, and the Rac and cdc42 guanine nucleotide exchange factor, Vav. SHIP is believed to act as a tumor suppressor during leukemogenesis and lymphomagenesis, and may play a role in activating the immune system to combat cancer. SHIP contains an N-terminal SH2 domain, a centrally located phosphatase domain that specifically hydrolyzes the 5'-phosphate from PIP3, PI-4,5-P2 and inositol-1,3,4,5- tetrakisphosphate (IP4), a C2 domain, that is an allosteric activating site when bound by SHIP's enzymatic product, PI-3,4-P2; 2 NPXY motifs that bind proteins with a phosphotyrosine binding (Shc, Dok 1, Dok 2) or an SH2 (p85a, SHIP2) domain; and a proline-rich domain consisting of four PxxP motifs that bind a subset of SH3-containing proteins including Grb2, Src, Lyn, Hck, Abl, PLCg1, and PIAS1. The SH2 domain of SHIP binds to the tyrosine phosphorylated forms of Shc, SHP-2, Doks, Gabs, CD150, platelet-endothelial cell adhesion molecule, Cas, c-Cbl, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs). The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX(V/I), which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 281361450 454 SSQFWYKPNLTREDAIALLASA-QPGTFLVRDSTTYKDSYGLVV 496
Cdd:cd10343    1 MAPPWYHGNITRSKAEELLSKAgKDGSFLVRDSESVSGAYALCV 44

Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, Fgr; Fgr is a member of the Src non-receptor type tyrosine kinase family of proteins. The protein contains N-terminal sites for myristoylation and palmitoylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. Fgr is expressed in B-cells and myeloid cells, localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Multiple alternatively spliced variants, encoding the same protein, have been identified Fgr has been shown to interact with Wiskott-Aldrich syndrome protein. Fgr has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 281361450 458 WYKPNLTREDA-IALLASAQP-GTFLVRDSTTYKDSYGLVVR 497
Cdd:cd10367    5 WYFGKIGRKDAeRQLLSPGNPrGAFLIRESETTKGAYSLSIR 46

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is part of a growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases, including Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, RasGEF, Smg GDS, and phospholipase C(epsilon). 12102558 21262352 BCAR3 binds to the carboxy-terminus of BCAR1/p130Cas, a focal adhesion adapter protein. Over expression of BCAR1 (p130Cas) and BCAR3 induces estrogen independent growth in normally estrogen-dependent cell lines. They have been linked to resistance to anti-estrogens in breast cancer, Rac activation, and cell motility, though the BCAR3/p130Cas complex is not required for this activity in BCAR3. Many BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. Structurally these proteins contain a single SH2 domain upstream of their RasGEF domain, which is responsible for the ability of BCAR3 to enhance p130Cas over-expression-induced migration. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281361450 454 SSQFWYKPNLTREDAIALLAsaQPGTFLVRDSTTYKDSYGLVVRvsqpppgSQELVRHFLIepTKGGVHLKG-------- 525
Cdd:cd10337    4 RSHAWYHGRIPRQVAESLVQ--REGDFLVRDSLSSPGDYVLTCR-------WKGQPLHFKI--NRVVLRPSEaytrvqyq 72

                         90
                 ....*....|....
gi 281361450 526 CDDEPvFTSLSALV 539
Cdd:cd10337   73 FEDEQ-FDSIPALV 85