Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. 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 1622934387 246 QSWQHQPEKLIFESCGYEANYLGSMLIKDLRGTESTQDACAKMRKSTEHMKKIPTIILSITYKGVKFIDASNKNVIAEHE 325
Cdd:cd01274     1 TQWRHSPEKLITGSVNYEAHYLGSTEIKELRGTESTKKAIQKLKKSTREMKKIPTIILSISYKGVKFIDATTKNLICEHE 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387 326 IRNISCAAQDPEDLCTFAYITKDLQTSHHYCHVFSTVDVNLTYEIILTLGQAFEVAYQLALQAQKS 391
Cdd:cd01274    81 IRNISCACQDPEDLNTFAYITKDLKTDHHYCHVFCVLTVDLATEIILTLGQAFEVAYQLALRAQKS 146

SAM domain of AIDA1AB-like proteins, repeat 2; SAM (sterile alpha motif) domain repeat 2 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of the SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM domains of the AIDA1AB-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNVLKVQLLGHRKRIIASLADR 152
Cdd:cd09500     1 DGNSPASVSEWLDSIGLGDYIETFLKHGYTSMERVKRIWEVELTNVLEINKLGHRKRILASLADR 65

Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. 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 1622934387 246 QSWQHQPEKLIFESCGYEANYLGSMLIKDLRGTESTQDACAKMRKSTEHMKKIPTIILSITYKGVKFIDASNKNVIAEHE 325
Cdd:cd01274     1 TQWRHSPEKLITGSVNYEAHYLGSTEIKELRGTESTKKAIQKLKKSTREMKKIPTIILSISYKGVKFIDATTKNLICEHE 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387 326 IRNISCAAQDPEDLCTFAYITKDLQTSHHYCHVFSTVDVNLTYEIILTLGQAFEVAYQLALQAQKS 391
Cdd:cd01274    81 IRNISCACQDPEDLNTFAYITKDLKTDHHYCHVFCVLTVDLATEIILTLGQAFEVAYQLALRAQKS 146

SAM domain of AIDA1AB-like proteins, repeat 2; SAM (sterile alpha motif) domain repeat 2 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of the SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM domains of the AIDA1AB-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNVLKVQLLGHRKRIIASLADR 152
Cdd:cd09500     1 DGNSPASVSEWLDSIGLGDYIETFLKHGYTSMERVKRIWEVELTNVLEINKLGHRKRILASLADR 65

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387 262 YEANYLGSM-------LIKDLRgTESTQDA--CAKM------RKSTEHMKKIPTIILSITYKGVKFIDASNKNVIAEHEI 326
Cdd:pfam00640   1 FAVRYLGSVevpeeraPDKNTR-MQQAREAirRVKAakinkiRGLSGETGPGTKVDLFISTDGLKLLNPDTQELIHDHPL 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387 327 RNIS-CAAQDPEDLCTFAYITKDLQTSHHYCHVFSTVDvnLTYEIILTLGQAFEVA 381
Cdd:pfam00640  80 VSISfCADGDPDLMRYFAYIARDKATNKFACHVFESED--GAQDIAQSIGQAFALA 133

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFlSSGYSSIDTVKNLWELELVNvLKVQLLGHRKRIIASL 149
Cdd:pfam00536   1 DGWSVEDVGEWLESIGLGQYIDSF-RAGYIDGDALLQLTEDDLLK-LGVTLLGHRKKILYAI 60

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622934387   87 YDGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVkNLWELELVNVLKVQLLGHRKRIIASL 149
Cdd:smart00454   1 VSQWSPESVADWLESIGLEQYADNFRKNGIDGALLL-LLTSEEDLKELGITKLGHRKKILKAI 62

Ankyrin repeat and sterile alpha motif (SAM) domain-containing (Anks) protein family Phosphotyrosine-binding (PTB) domain; Both AIDA-1b (AbetaPP intracellular domain-associated protein 1b) and Odin (also known as ankyrin repeat and sterile alpha motif domain-containing 1A; ANKS1A) belong to the Anks protein family. Both of these family members interacts with the EphA8 receptor. Ank members consists of ankyrin repeats, a SAM domain and a C-terminal PTB domain which is crucial for interaction with the juxtamembrane (JM) region of EphA8. PTB domains are classified into three groups, namely, phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains of which the Anks PTB is a member. 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 1622934387 246 QSWQHQPEKLIFESCGYEANYLGSMLIKDLRGTESTQDACAKMRKSTEHMKKIPTIILSITYKGVKFIDASNKNVIAEHE 325
Cdd:cd01274     1 TQWRHSPEKLITGSVNYEAHYLGSTEIKELRGTESTKKAIQKLKKSTREMKKIPTIILSISYKGVKFIDATTKNLICEHE 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387 326 IRNISCAAQDPEDLCTFAYITKDLQTSHHYCHVFSTVDVNLTYEIILTLGQAFEVAYQLALQAQKS 391
Cdd:cd01274    81 IRNISCACQDPEDLNTFAYITKDLKTDHHYCHVFCVLTVDLATEIILTLGQAFEVAYQLALRAQKS 146

SAM domain of AIDA1AB-like proteins, repeat 2; SAM (sterile alpha motif) domain repeat 2 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of the SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM domains of the AIDA1AB-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNVLKVQLLGHRKRIIASLADR 152
Cdd:cd09500     1 DGNSPASVSEWLDSIGLGDYIETFLKHGYTSMERVKRIWEVELTNVLEINKLGHRKRILASLADR 65

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 1622934387 260 CGYEANYLGSMLIKDLRGTESTQDACAKMRKSTEHMKKIPT-IILSITYKGVKFIDASNKNVIAEHEIRNISCAAQDPED 338
Cdd:cd00934     1 ASFQVKYLGSVEVGSSRGVDVVEEALKALAAALKSSKRKPGpVLLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRDPDN 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1622934387 339 LCTFAYITKDLQTSHHYCHVFSTVDVNLTYEIILTLGQAF 378
Cdd:cd00934    81 PNVFAFIAGEEGGSGFRCHVFQCEDEEEAEEILQAIGQAF 120

SAM domain of Ship2 lipid phosphatase proteins; SAM (sterile alpha motif) domain of Ship2 subfamily is a protein-protein interaction domain. Ship2 proteins are lipid phosphatases (Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2) containing an N-terminal SH2 domain, a central phosphatase domain and a C-terminal SAM domain. Ship2 is involved in a number of PI3K signaling pathways. For example, it plays a role in regulation of the actin cytoskeleton remodeling, in insulin signaling pathways, and in EphA2 receptor endocytosis. SAM domain of Ship2 can interact with SAM domain of other proteins in these pathways, thus participating in signal transduction. In particular, SAM of Ship2 is known to form heterodimers with SAM domain of Eph-A2 receptor tyrosine kinase during receptor endocytosis as well as with SAM domain of PI3K effector protein Arap3 in the actin cytoskeleton signaling network. Since Ship2 plays a role in negatively regulating insulin signaling, it has been suggested that inhibition of its expression or function may contribute in treating type 2 diabetes and obesity-induced insulin resistance.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387  14 SRTLEQSVGEWLESIGLQQYESKLLLNGFDDVRFLGSnVMEEqDLRDIGISDPQHRRKLL 73
Cdd:cd09491     1 SLSWPKTVSEWLMNLGLQQYEEGLMHNGWDSLEFLSD-ITEE-DLEEAGVTNPAHKRRLL 58

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387 262 YEANYLGSM-------LIKDLRgTESTQDA--CAKM------RKSTEHMKKIPTIILSITYKGVKFIDASNKNVIAEHEI 326
Cdd:pfam00640   1 FAVRYLGSVevpeeraPDKNTR-MQQAREAirRVKAakinkiRGLSGETGPGTKVDLFISTDGLKLLNPDTQELIHDHPL 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387 327 RNIS-CAAQDPEDLCTFAYITKDLQTSHHYCHVFSTVDvnLTYEIILTLGQAFEVA 381
Cdd:pfam00640  80 VSISfCADGDPDLMRYFAYIARDKATNKFACHVFESED--GAQDIAQSIGQAFALA 133

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387 262 YEANYLGSMLIKDLRGTESTQDACA---KMRKSTEhmKKIPTIILSITYKGVKFIDASNKNVIAEHEIRNIS-CAAqDPE 337
Cdd:cd13159     5 FYLKYLGSTLVEKPKGEGATAEAVKtiiAMAKASG--KKLQKVTLTVSPKGIKVTDSATNETILEVSIYRISyCTA-DAN 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1622934387 338 DLCTFAYITKDLQTSHHYCHVFSTVDVNLTYEIILTLGQAFE 379
Cdd:cd13159    82 HDKVFAFIATNQDNEKLECHAFLCAKRKMAQAVTLTVAQAFN 123

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622934387  19 QSVGEWLESIGLQQYEsKLLLNGFDDVRFLGSnvMEEQDLRDIGISDPQHRRKLLQAARSL 79
Cdd:pfam00536   6 EDVGEWLESIGLGQYI-DSFRAGYIDGDALLQ--LTEDDLLKLGVTLLGHRKKILYAIQRL 63

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622934387   87 YDGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVkNLWELELVNVLKVQLLGHRKRIIASL 149
Cdd:smart00454   1 VSQWSPESVADWLESIGLEQYADNFRKNGIDGALLL-LLTSEEDLKELGITKLGHRKKILKAI 62

SAM (Sterile alpha motif ); SAM (Sterile Alpha Motif) domain is a module consisting of approximately 70 amino acids. This domain is found in the Fungi/Metazoa group and in a restricted number of bacteria. Proteins with SAM domains are represented by a wide variety of domain architectures and have different intracellular localization, including nucleus, cytoplasm and membranes. SAM domains have diverse functions. They can interact with proteins, RNAs and membrane lipids, contain site of phosphorylation and/or kinase docking site, and play a role in protein homo and hetero dimerization/oligomerization in processes ranging from signal transduction to regulation of transcription. Mutations in SAM domains have been linked to several diseases.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1622934387  20 SVGEWLESIGLQQYESKLLLNGFDDVRFLgsnVMEEQDLRDIGISDPQHRRKLLQAAR 77
Cdd:cd09487     1 DVAEWLESLGLEQYADLFRKNEIDGDALL---LLTDEDLKELGITSPGHRKKILRAIQ 55

Tensin-related Phosphotyrosine-binding (PTB) domain; Tensin plays critical roles in renal function, muscle regeneration, and cell migration. It binds to actin filaments and interacts with the cytoplasmic tails of beta-integrin via its PTB domain, allowing tensin to link actin filaments to integrin receptors. Tensin functions as a platform for assembly and disassembly of signaling complexes at focal adhesions by recruiting tyrosine-phosphorylated signaling molecules, and also by providing interaction sites for other proteins. In addition to its PTB domain, it contains a C-terminal SH2 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387 264 ANYLGSMLIKDLrgteSTQDACAKMRKSTEHMKKIPT----IILSITYKGVKFIDASNKNVIAEHEIRNISCAAQDPEDl 339
Cdd:cd13157     6 AQYIGSFPVSGL----DVADRADSVRKQLESLKESGSrgrpVILSVSLSGIKICSEDGKVVLMAHALRRVSYSTCRPAH- 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1622934387 340 CTFAYITKDLQ--TSHHYCHVFSTVDVNLTYEIILTLGQAFEVAY 382
Cdd:cd13157    81 AQFAFVARNPGgpTNRQYCHVFVTRSPREAQELNLLLCRAFQLAY 125

SAM domain of EPH family of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH (erythropoietin-producing hepatocyte) family of receptor tyrosine kinases is a C-terminal signal transduction module located in the cytoplasmic region of these receptors. SAM appears to mediate cell-cell initiated signal transduction via binding proteins to a conserved tyrosine that is phosphorylated. In some cases the SAM domain mediates homodimerization/oligomerization and plays a role in the clustering process necessary for signaling. EPH kinases are the largest family of receptor tyrosine kinases. They are classified into two groups based on their abilities to bind ephrin-A and ephrin-B ligands. The EPH receptors are involved in regulation of cell movement, shape, and attachment during embryonic development; they control cell-cell interactions in the vascular, nervous, epithelial, and immune systems, and in many tumors. They are potential molecular markers for cancer diagnostics and potential targets for cancer therapy.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1622934387  91 SPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNvLKVQLLGHRKRIIASL 149
Cdd:cd09488     1 AFRSVGEWLESIKMGRYKENFTAAGYTSLDAVAQMTAEDLTR-LGVTLVGHQKKILNSI 58

SAM domain of caskin protein repeat 2; SAM (sterile alpha motif) domain repeat 2 of caskin1,2 proteins is a protein-protein interaction domain. Caskin has two tandem SAM domains. Caskin protein is known to interact with membrane-associated guanylate kinase CASK, and may play a role in neural development, synaptic protein targeting, and regulation of gene expression.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387  89 GNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNL-WE-LElvnVLKVQLLGHRKRII 146
Cdd:cd09498     4 DYPPNDLLEWLSLLGLPQYHKVLVENGYDSIDFVTDLtWEdLQ---DIGITKLGHQKKLM 60

SAM domain of SAMSN1 subfamily; SAM (sterile alpha motif) domain of SAMSN1 (also known as HACS1 or NASH1) proteins is a predicted protein-protein interaction domain. Members of this group are putative signaling/adaptor proteins. They appear to mediate signal transduction in lymphoid tissues. Murine HACS1 protein likely plays a role in B cell activation and differentiation. Potential binding partners of HACS1 are SLAM, DEC205 and PIR-B receptors and also some unidentified tyrosine-phosphorylated proteins. Proteins of this group were found preferentially expressed in normal hematopietic tissues and in some malignancies including lymphoma, myeloid leukemia and myeloma.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622934387  15 RTLEQSVGEWLESIGLQQYESKLLLNGFDDVRFLGSnvMEEQDLRDIGISDPQHRRKLLQAARSL 79
Cdd:cd09561     2 RPKPKTLQELLERIHLQEYTSTLLLNGYETLEDLKD--LKESHLIELNITDPEDRARLLSAAENL 64

SAM domain of SASH1 proteins, repeat 2; SAM (sterile alpha motif) repeat 2 of SASH1 proteins is a protein-protein interaction domain. Members of this subfamily are putative adaptor proteins. They appear to mediate signal transduction. SASH1 can bind 14-3-3 proteins in response to IGF1/phosphatidylinositol 3-kinase signaling. SASH1 was found upregulated in different tissues including thymus, placenta, lungs and downregulated in some breast tumors, liver metastases and colon cancers if compare to corresponding normal tissues. SASH1 is a potential candidate for a tumor suppressor gene in breast cancers. At the same time, downregulation of SASH1 in colon cancer is associated with metastasis and a poor prognosis.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387  20 SVGEWLESIGLQQYESKLLLNGFDDVRFLGSnvMEEQDLRDIGISDPQHRRKLLQAARSL 79
Cdd:cd09492     9 SVSDWLVSIGLPMYSPPLLEAGFSTLSRVSS--LSETCLREAGITEERHIRKLLSAARLV 66

Disabled (Dab) Phosphotyrosine-binding domain; Dab is a cystosolic adaptor protein, which binds to the cytoplasmic tails of lipoprotein receptors, such as ApoER2 and VLDLR, via its PTB domain. The dab PTB domain has a preference for unphosphorylated tyrosine within an NPxY motif. Additionally, the Dab PTB domain, which is structurally similar to PH domains, binds to phosphatidlyinositol phosphate 4,5 bisphosphate in a manner characteristic of phosphoinositide binding PH domains. 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 1622934387 262 YEANYLGSMLIKDLRGTESTQDACAKM----RKSTEHMKKIptiILSITYKGVKFIDASNKNVIAEHEIRNISCAAQDPE 337
Cdd:cd01215    18 FKAKLIGIDEVPAARGDKMCQDAMMKLkgavKAAGEHKQRI---WLNISLEGIKILDEKTGALLHHHPVHKISFIARDTT 94

                          90
                  ....*....|....*...
gi 1622934387 338 DLCTFAYITKdLQTSHHY 355
Cdd:cd01215    95 DNRAFGYVCG-LDGGHRF 111

SAM domain of caskin protein repeat 2; SAM (sterile alpha motif) domain repeat 2 of caskin1,2 proteins is a protein-protein interaction domain. Caskin has two tandem SAM domains. Caskin protein is known to interact with membrane-associated guanylate kinase CASK, and may play a role in neural development, synaptic protein targeting, and regulation of gene expression.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387  20 SVGEWLESIGLQQYESKLLLNGFDDVRFLGSNVMEeqDLRDIGISDPQHRRKLLQAARSL 79
Cdd:cd09498     9 DLLEWLSLLGLPQYHKVLVENGYDSIDFVTDLTWE--DLQDIGITKLGHQKKLMLAIKKL 66

SAM domain of SASH1 proteins, repeat 1; SAM (sterile alpha motif) repeat 1 of SASH1 proteins is a predicted protein-protein interaction domain. Members of this subfamily are putative adaptor proteins. They appear to mediate signal transduction. SASH1 can bind 14-3-3 proteins in response to IGF1/phosphatidylinositol 3-kinase signaling. SASH1 was found upregulated in different tissues including thymus, placenta, lungs and downregulated in some breast tumors, liver metastases and colon cancers, relative to corresponding normal tissues. SASH1 is a potential candidate for a tumor suppressor gene in breast cancers. At the same time, downregulation of SASH1 in colon cancer is associated with metastasis and a poor prognosis.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622934387  19 QSVGEWLESIGLQQYESKLLLNGFDDVRFLgsNVMEEQDLRDIGISDPQHRRKLLQAARSL 79
Cdd:cd09559     4 KSVEDLLDRINLKEHMPTFLFNGYEDLDTF--KLLEEEDLDELNIRDPEHRAVLLTAVELL 62

SAM domain of diacylglycerol kinase delta and eta subunits; SAM (sterile alpha motif) domain of DGK-eta-delta subfamily proteins is a protein-protein interaction domain. Proteins of this subfamily are multidomain diacylglycerol kinases with a SAM domain located at the C-terminus. DGK proteins participate in signal transduction. They regulate the level of second messengers such as diacylglycerol and phosphatidic acid. The SAM domain of DGK proteins can form high molecular weight homooligomers through head-to-tail interactions as well as heterooligomers between the SAM domains of DGK delta and eta proteins. The oligomerization plays a role in the regulation of DGK intracellular localization.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622934387  21 VGEWLESIGLQQYESKLLLNgfdDVRflGSNVM--EEQDLRDIGISDPQHRRKLLQAARSL 79
Cdd:cd09507    10 VGAWLESLQLGEYRDIFARN---DIR--GSELLhlERRDLKDLGITKVGHVKRILQAIKDL 65

SAM domain of EPH-B3 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B3 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B3 receptors and appears to mediate cell-cell initiated signal transduction. EPH-B3 receptor protein kinase performs kinase-dependent and kinase-independent functions. It is known to be involved in thymus morphogenesis, in regulation of cell adhesion and migration. Also EphB3 controls cell positioning and ordered migration in the intestinal epithelium and plays a role in the regulation of adult retinal ganglion cell axon plasticity after optic nerve injury. In some experimental models overexpression of EphB3 enhances cell/cell contacts and suppresses colon tumor growth.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNVlKVQLLGHRKRIIASLAD 151
Cdd:cd09553     2 DYTTFTTVGDWLDAIKMGRYKENFVSAGFASFDLVAQMTAEDLLRI-GVTLAGHQKKILSSIQD 64

SAM domain of SARM1-like, repeat 2; SAM (sterile alpha motif) domain repeat 2 of SARM1-like adaptor proteins is a protein-protein interaction domain. SARM1-like proteins contain two tandem SAM domains. SARM1-like proteins are involved in TLR (Toll-like receptor) signaling. They are responsible for targeted localization of the whole protein to post-synaptic regions of axons. In humans SARM1 expression is detected in kidney and liver.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1622934387  23 EWLESIG--LQQYESKLLLNGFDdvRFLGSNVMEEQDLRDIGISDPQHRRKLLQAAR 77
Cdd:cd09502    12 NWLQSLGpeYSQYTYQMLNAGID--RNSLPSLTEDQLLEDCGITNGIHRLRILNAIK 66

SAM domain of EPH-B4 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B4 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B4 receptors and appears to mediate cell-cell initiated signal transduction. EPH-B4 protein kinase performs kinase-dependent and kinase-independent functions. These receptors play a role in the regular vascular system development during embryogenesis. They were found overexpressed in a variety of cancers, including carcinoma of the head and neck, ovarian cancer, bladder cancer, and downregulated in bone myeloma. Thus, EphB4 is a potential biomarker and a target for drug design.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387  94 SVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNvLKVQLLGHRKRIIASL 149
Cdd:cd09554     5 SVGEWLRAIKMERYEDSFLQAGFTTFQLVSQISTEDLLR-MGVTLAGHQKKILSSI 59

SAM domain of EPH family of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH (erythropoietin-producing hepatocyte) family of receptor tyrosine kinases is a C-terminal signal transduction module located in the cytoplasmic region of these receptors. SAM appears to mediate cell-cell initiated signal transduction via binding proteins to a conserved tyrosine that is phosphorylated. In some cases the SAM domain mediates homodimerization/oligomerization and plays a role in the clustering process necessary for signaling. EPH kinases are the largest family of receptor tyrosine kinases. They are classified into two groups based on their abilities to bind ephrin-A and ephrin-B ligands. The EPH receptors are involved in regulation of cell movement, shape, and attachment during embryonic development; they control cell-cell interactions in the vascular, nervous, epithelial, and immune systems, and in many tumors. They are potential molecular markers for cancer diagnostics and potential targets for cancer therapy.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1622934387  20 SVGEWLESIGLQQYESKLLLNGF---DDVRFlgsnvMEEQDLRDIGISDPQHRRKLL 73
Cdd:cd09488     4 SVGEWLESIKMGRYKENFTAAGYtslDAVAQ-----MTAEDLTRLGVTLVGHQKKIL 55

SAM domain of EPH-A8 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A8 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A8 receptors and appears to mediate cell-cell initiated signal transduction. EPH-A8 receptors are involved in ligand dependent (ephirin A2, A3, A5) regulation of cell adhesion and migration, and in ligand independent regulation of neurite outgrowth in neuronal cells. They perform signaling in kinase dependent and kinase independent manner. EPH-A8 receptors are known to interact with a number of different proteins including PI 3-kinase and AIDA1-like subfamily SAM repeat domain containing proteins. However other domains (not SAM) of EPH-A8 receptors are involved in these interactions.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387  94 SVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLwELELVNVLKVQLLGHRKRIIASL 149
Cdd:cd09550     4 SVDDWLDSIKMGRYKDHFAAGGYSSLGMVMRM-NIEDIRRLGITLMGHQKKILTSI 58

SAM domain of EPH-A1 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A1 subfamily of the receptor tyrosine kinases is a C-terminal protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A1 receptors and appears to mediate cell-cell initiated signal transduction. Activation of these receptors leads to inhibition of cell spreading and migration in a RhoA-ROCK-dependent manner. EPH-A1 receptors are known to bind ILK (integrin-linked kinase) which is the mediator of interactions between integrin and the actin cytoskeleton. However SAM is not sufficient for this interaction; it rather plays an ancillary role. SAM domains of Eph-A1 receptors do not form homo/hetero dimers/oligomers. EphA1 gene was found expressed widely in differentiated epithelial cells. In a number of different malignant tumors EphA1 genes are downregulated. In breast carcinoma the downregulation is associated with invasive behavior of the cell.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1622934387  94 SVPSWLDSLGLQDYVHSFLSSGyssIDTVKNLWEL--ELVNVLKVQLLGHRKRIIASL 149
Cdd:cd09542     6 SVSEWLESIRMKRYILHFRSAG---LDTMECVLELtaEDLTQMGITLPGHQKRILCSI 60

SAM domain of EPH-B2 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B2 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B2 receptors and appears to mediate cell-cell initiated signal transduction. SAM domains of this subfamily form homodimers/oligomers (in head-to-head/tail-to-tail orientation); apparently such clustering is necessary for signaling. EPH-B2 receptor is involved in regulation of synaptic function; it is needed for normal vestibular function, proper formation of anterior commissure, control of cell positioning, and ordered migration in the intestinal epithelium. EPH-B2 plays a tumor suppressor role in colorectal cancer. It was found to be downregulated in gastric cancer and thus may be a negative biomarker for it.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNVlKVQLLGHRKRIIASL 149
Cdd:cd09552     2 DYTSFSTVDEWLDAIKMGQYKESFANAGFTSFDVVSQMTMEDILRV-GVTLAGHQKKILNSI 62

SAM domain of EPH-B1 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B1 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH- B1 receptors. In human vascular endothelial cells it appears to mediate cell-cell initiated signal transduction via the binding of the adaptor protein GRB10 (growth factor) through its SH2 domain to a conserved tyrosine that is phosphorylated. EPH-B1 receptors play a role in neurogenesis, in particular in regulation of proliferation and migration of neural progenitors in the hippocampus and in corneal neovascularization; they are involved in converting the crossed retinal projection to ipsilateral retinal projection. They may be potential targets in angiogenesis-related disorders.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622934387  88 DGNSPPSVPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELVNVlKVQLLGHRKRIIASL 149
Cdd:cd09551     2 DFTAFTSVEDWLSAIKMSQYRDNFLSSGFTSLQLVAQMTSEDLLRI-GVTLAGHQKKILNSI 62

SAM domain of Ste50_like (ubc2) subfamily; SAM (sterile alpha motif) domain of Ste50-like (or Ubc2 for Ustilago bypass of cyclase) subfamily is a putative protein-protein interaction domain. This group includes only fungal proteins. Basidiomycetes have an N-terminal SAM domain, central UBQ domain, and C-terminal SH3 domain, while Ascomycetes lack the SH3 domain. Ubc2 of Ustilago maydis is a major virulence and maize pathogenicity factor. It is required for filamentous growth (the budding haploid form of Ustilago maydis is a saprophyte, while filamentous dikaryotic form is a pathogen). Also the Ubc2 protein is involved in the pheromone-responsive morphogenesis via the MAP kinase cascade. The SAM domain is necessary for ubc2 function; deletion of SAM eliminates this function. A Lys-to-Glu mutation in the SAM domain of ubc2 gene induces temperature sensitivity.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622934387  21 VGEWLESIGLQQYESKLLLNGFD-DVRFLgsnvMEEQDLRDIGISDPQHRRKLLQA 75
Cdd:cd09533     2 VADWLSSLGLPQYEDQFIENGITgDVLVA----LDHEDLKEMGITSVGHRLTILKA 53

SAM domain of EPH-B1 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B1 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH- B1 receptors. In human vascular endothelial cells it appears to mediate cell-cell initiated signal transduction via the binding of the adaptor protein GRB10 (growth factor) through its SH2 domain to a conserved tyrosine that is phosphorylated. EPH-B1 receptors play a role in neurogenesis, in particular in regulation of proliferation and migration of neural progenitors in the hippocampus and in corneal neovascularization; they are involved in converting the crossed retinal projection to ipsilateral retinal projection. They may be potential targets in angiogenesis-related disorders.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622934387  20 SVGEWLESIGLQQYESKLLLNGFDDVRFLGSnvMEEQDLRDIGISDPQHRRKLLQAARSL 79
Cdd:cd09551     8 SVEDWLSAIKMSQYRDNFLSSGFTSLQLVAQ--MTSEDLLRIGVTLAGHQKKILNSIQSM 65

SAM domain of Samd5 subfamily; SAM (sterile alpha motif) domain of Samd5 subfamily is a putative protein-protein interaction domain. Proteins of this subfamily have a SAM domain at the N-terminus. SAM is a widespread domain in signaling and regulatory proteins. In many cases SAM mediates dimerization/oligomerization. The exact function of proteins belonging to this subfamily is unknown.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1622934387  95 VPSWLDSLGLQDYVHSFLSSGYSSIDTVKNLWELELvNVLKVQLLGHRKRI 145
Cdd:cd09527     5 VYDWLRTLQLEQYAEKFVDNGYDDLEVCKQIGDPDL-DAIGVMNPAHRKRI 54

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1622934387  20 SVGEWLESIGLQQYESKLLLNGFDDVR-FLGSNvmeEQDLRDIGISDPQHRRKLL 73
Cdd:cd09490     5 DIAEWLASIHLEQYLDLFREHGYVTATdCQGIN---DSRLKQIGISPTGHRRRIL 56

GTPase activating protein for Rab 6 Phosphotyrosine-binding (PTB) domain; GAPCenA is a centrosome-associated GTPase activating protein (GAP) for Rab 6. It consists of an N-terminal PTB domain and a C-terminal TBC 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 1622934387 266 YLGSMLIKDLRGTESTQDACAKMRKSTEhmKKIPtIILSI--TYKG-VKFIDASNKNVIAEHEIRNIS-CA---AQDPED 338
Cdd:cd01211     8 YLGCAKVNAPRSETEALRIMAILREQSA--QPIK-VTLSVpnSSEGsVRLYDPTSNTEIASYPIYRILfCArgpDGTSES 84

                          90       100
                  ....*....|....*....|...
gi 1622934387 339 LCtFAYITKDLQTSHHYCHVFST 361
Cdd:cd01211    85 DC-FAFTWSHGETAIFQCHVFRC 106