Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 67846032 447 TSKYWLKPSITREQAINLLRTEKPGTFVIRDSSSYRGSFGLALKVQETP--ASAPNRPGEDSTDFIRHFLVESSAKGVHL 524
Cdd:cd09927   1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPpgVNPFEAKGDPESELVRHFLIEPSPKGVKL 80

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 67846032 525 KGADEEPYFGSLSAFVCQHSIMALALPCKLTIPQKE 560
Cdd:cd09927  81 KGCPNEPVFGSLSALVYQHSITPLALPCKLRIPDRD 116

Src homology 2 domain found in Tensin-like proteins; SH2 domain found in Tensin-like proteins. The Tensins are a family of intracellular proteins that interact with receptor tyrosine kinases (RTKs), integrins, and actin. They are thought act as signaling bridges between the extracellular space and the cytoskeleton. There are four homologues: Tensin1, Tensin2 (TENC1, C1-TEN), Tensin3 and Tensin4 (cten), all of which contain a C-terminal tandem SH2-PTB domain pairing, as well as actin-binding regions that may localize them to focal adhesions. The isoforms of Tensin2 and Tensin3 contain N-terminal C1 domains, which are atypical and not expected to bind to phorbol esters. Tensins 1-3 contain a phosphatase (PTPase) and C2 domain pairing which resembles PTEN (phosphatase and tensin homologue deleted on chromosome 10) protein. PTEN is a lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to yield phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). As PtdIns(3,4,5)P3 is the product of phosphatidylinositol 3-kinase (PI3K) activity, PTEN is therefore a key negative regulator of the PI3K pathway. Because of their PTEN-like domains, the Tensins may also possess phosphoinositide-binding or phosphatase capabilities. However, only Tensin2 and Tensin3 have the potential to be phosphatases since only their PTPase domains contain a cysteine residue that is essential for catalytic activity. 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 67846032 447 TSKYWLKPSITREQAINLLRTEKPGTFVIRDSSSYRGSFGLALKVQETP--ASAPNRPGEDSTDFIRHFLVESSAKGVHL 524
Cdd:cd09927   1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPpgVNPFEAKGDPESELVRHFLIEPSPKGVKL 80

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 67846032 525 KGADEEPYFGSLSAFVCQHSIMALALPCKLTIPQKE 560
Cdd:cd09927  81 KGCPNEPVFGSLSALVYQHSITPLALPCKLRIPDRD 116

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 67846032    585 CHTLYLTSVSVETLSGALAVQKAISVMLERD--VLPTPTVVHFKVTEQGITLTDVQRKvFFRRHYPLIALRFCGMDPEQr 662
Cdd:smart00462   6 FRVKYLGSVEVPEARGLQVVQEAIRKLRAAQgsEKKEPQKVILSISSRGVKLIDEDTK-AVLHEHPLRRISFCAVGPDD- 83

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 67846032    663 kwqkyckpSRIFGFVAKSQTEpQENACHLFAEYDAAQPASQVI 705
Cdd:smart00462  84 --------LDVFGYIARDPGS-SRFACHVFRCEKAAEDIALAI 117

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 67846032   451 WLKPSITREQAINLLRTEKP-GTFVIRDSSSYRGSFGLALKVQETpasapnrpgedstdfIRHFLVESSAKGVHLKGadE 529
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPdGTFLVRESESTPGGYTLSVRDDGK---------------VKHYKIQSTDNGGYYIS--G 63

                          90
                  ....*....|.
gi 67846032   530 EPYFGSLSAFV 540
Cdd:pfam00017  64 GVKFSSLAELV 74

Src homology 2 domain found in Tensin-like proteins; SH2 domain found in Tensin-like proteins. The Tensins are a family of intracellular proteins that interact with receptor tyrosine kinases (RTKs), integrins, and actin. They are thought act as signaling bridges between the extracellular space and the cytoskeleton. There are four homologues: Tensin1, Tensin2 (TENC1, C1-TEN), Tensin3 and Tensin4 (cten), all of which contain a C-terminal tandem SH2-PTB domain pairing, as well as actin-binding regions that may localize them to focal adhesions. The isoforms of Tensin2 and Tensin3 contain N-terminal C1 domains, which are atypical and not expected to bind to phorbol esters. Tensins 1-3 contain a phosphatase (PTPase) and C2 domain pairing which resembles PTEN (phosphatase and tensin homologue deleted on chromosome 10) protein. PTEN is a lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to yield phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). As PtdIns(3,4,5)P3 is the product of phosphatidylinositol 3-kinase (PI3K) activity, PTEN is therefore a key negative regulator of the PI3K pathway. Because of their PTEN-like domains, the Tensins may also possess phosphoinositide-binding or phosphatase capabilities. However, only Tensin2 and Tensin3 have the potential to be phosphatases since only their PTPase domains contain a cysteine residue that is essential for catalytic activity. 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 67846032 447 TSKYWLKPSITREQAINLLRTEKPGTFVIRDSSSYRGSFGLALKVQETP--ASAPNRPGEDSTDFIRHFLVESSAKGVHL 524
Cdd:cd09927   1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPpgVNPFEAKGDPESELVRHFLIEPSPKGVKL 80

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 67846032 525 KGADEEPYFGSLSAFVCQHSIMALALPCKLTIPQKE 560
Cdd:cd09927  81 KGCPNEPVFGSLSALVYQHSITPLALPCKLRIPDRD 116

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 67846032    585 CHTLYLTSVSVETLSGALAVQKAISVMLERD--VLPTPTVVHFKVTEQGITLTDVQRKvFFRRHYPLIALRFCGMDPEQr 662
Cdd:smart00462   6 FRVKYLGSVEVPEARGLQVVQEAIRKLRAAQgsEKKEPQKVILSISSRGVKLIDEDTK-AVLHEHPLRRISFCAVGPDD- 83

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 67846032    663 kwqkyckpSRIFGFVAKSQTEpQENACHLFAEYDAAQPASQVI 705
Cdd:smart00462  84 --------LDVFGYIARDPGS-SRFACHVFRCEKAAEDIALAI 117

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 67846032 588 LYLTSVSVETLSGALAVQKAISVMLE--RDVLPTPTVVHFKVTEQGITLTDVQRKVFFRRHyPLIALRFCGMDPEQrkwq 665
Cdd:cd00934   6 KYLGSVEVGSSRGVDVVEEALKALAAalKSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRH-PLHRISYCGRDPDN---- 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 67846032 666 kyckpSRIFGFVAKSQTEPQeNACHLFAEYDAAQpASQVISLV 708
Cdd:cd00934  81 -----PNVFAFIAGEEGGSG-FRCHVFQCEDEEE-AEEILQAI 116

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 67846032   451 WLKPSITREQAINLLRTEKP-GTFVIRDSSSYRGSFGLALKVQETpasapnrpgedstdfIRHFLVESSAKGVHLKGadE 529
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPdGTFLVRESESTPGGYTLSVRDDGK---------------VKHYKIQSTDNGGYYIS--G 63

                          90
                  ....*....|.
gi 67846032   530 EPYFGSLSAFV 540
Cdd:pfam00017  64 GVKFSSLAELV 74

C-terminal Src homology 2 (cSH2) 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, a inter 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 67846032 451 WLKPSITREQAINLLRTEKPGTFVIRDSSSyRGSFGLALKVQETpasapnrpgedstdfIRHFLVESSAKGVHLKgadeE 530
Cdd:cd09930   8 WLVGDINRTQAEELLRGKPDGTFLIRESST-QGCYACSVVCNGE---------------VKHCVIYKTETGYGFA----E 67

                        90
                ....*....|..
gi 67846032 531 PY--FGSLSAFV 540
Cdd:cd09930  68 PYnlYESLKELV 79

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; 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
                ....*....|....*....|....*....|....*....|....*....
gi 67846032 450 YWLKpsITREQAINLLRTEKPGTFVIRDSSSYRGSFGLALKVQETPASA 498
Cdd:cd09923   3 YWGG--ITRYEAEELLAGKPEGTFLVRDSSDSRYLFSVSFRTYGRTLHA 49

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 67846032 451 WLKPSITREQAINLLRTEKPGTFVIRDSSSYRGSFGLAL----KVQetpasapnrpgedstdfirHFLVESSAKGVHLkg 526
Cdd:cd09937   5 WFHGKISREEAERLLQPPEDGLFLVRESTNYPGDYTLCVsfegKVE-------------------HYRVIYRNGKLTI-- 63

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 67846032 527 aDEEPYFGSLSAFVCQHSIMALALPCKLTIPQKELG 562
Cdd:cd09937  64 -DEEEYFENLIQLVEHYTKDADGLCTRLVKPKVKEG 98

N-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 the 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
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 67846032 451 WLKPSITREQAINLLRTEKP--GTFVIRDSSSYRGSFGLALKVQETPASAP-NRPGED 505
Cdd:cd10347   3 WYHGKISREVAEALLLREGGrdGLFLVRESTSAPGDYVLSLLAQGEVLHYQiRRHGED 60

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine kinase Txk is expressed in thymus, spleen, lymph node, T lymphocytes, NK cells, mast cell lines, and myeloid cell line. Txk plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain. Txk also has a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. 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 67846032 451 WLKPSITREQAINLLRTE-KPGTFVIRDsSSYRGSFGLalkvqetpaSAPNRPGEDSTDFIRHFLVESSAKGVHLkgADE 529
Cdd:cd10398   8 WYHKNITRNQAERLLRQEsKEGAFIVRD-SRHLGSYTI---------SVFTRARRSTEASIKHYQIKKNDSGQWY--VAE 75

                        90       100
                ....*....|....*....|....*...
gi 67846032 530 EPYFGSLSAFVCQHSIMALALPCKLTIP 557
Cdd:cd10398  76 RHLFQSIPELIQYHQHNAAGLMSRLRYP 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 67846032 451 WLKPSITREQAINLLRTEK--PGTFVIRDSSSYRGSFGLALKVQETPasapnrpgedstdfiRHFLVESSAKGVHLkgAD 528
Cdd:cd10348   2 WLHGALDRNEAVEILKQKAdaDGSFLVRYSRRRPGGYVLTLVYENHV---------------YHFEIQNRDDKWFY--ID 64

                        90
                ....*....|....*
gi 67846032 529 EEPYFGSLSAFVcQH 543
Cdd:cd10348  65 DGPYFESLEHLI-EH 78

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 67846032 451 WLKPSITREQAINLLR--TEKPGTFVIRDSSSYRGSFGLALKvqetpasapnRPGEDSTDFIRHF 513
Cdd:cd10344  12 WLFEGLSREKAEELLMlpGNQVGSFLIRESETRRGCYSLSVR----------HRGSQSRDSVKHY 66