Pleckstrin homology domain-containing family G member 5 and 6 pleckstrin homology (PH) domain; PLEKHG5 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG5 activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in PLEKHG5 are associated with autosomal recessive distal spinal muscular atrophy. PLEKHG6 (also called MyoGEF) has no known function to date. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 408 RQLLLEGPVRVKEGREGKLDVYLFLFSDVLLVTKP-QRKVDKAKVIRPPLMLEKLVCQPLRDPHSFLLIHLTEFQCVSSA 486
Cdd:cd13244     1 RRLLLEGDLRLKEGKGSKVDVHCFLFTDMLLICKPvKRKKDRLKVIRPPYLVDKLVVQELKDPGGFLLVYLNEFHTAVAA 80

                          90       100
                  ....*....|....*....|
gi 1622843588 487 LIVQCPSPTDRARWLEKTQQ 506
Cdd:cd13244    81 YTFQTSSQEDTRRWLDAIRK 100

Pleckstrin homology domain-containing family G member 5 and 6 pleckstrin homology (PH) domain; PLEKHG5 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG5 activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in PLEKHG5 are associated with autosomal recessive distal spinal muscular atrophy. PLEKHG6 (also called MyoGEF) has no known function to date. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 408 RQLLLEGPVRVKEGREGKLDVYLFLFSDVLLVTKP-QRKVDKAKVIRPPLMLEKLVCQPLRDPHSFLLIHLTEFQCVSSA 486
Cdd:cd13244     1 RRLLLEGDLRLKEGKGSKVDVHCFLFTDMLLICKPvKRKKDRLKVIRPPYLVDKLVVQELKDPGGFLLVYLNEFHTAVAA 80

                          90       100
                  ....*....|....*....|
gi 1622843588 487 LIVQCPSPTDRARWLEKTQQ 506
Cdd:cd13244    81 YTFQTSSQEDTRRWLDAIRK 100

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  165 ALWELLTTELIYVRKLKIMTDLLAAGLLnlQRVGLLTEVSAETLFGNVPSLIRTHRSFWEEvlgptLEETRA-SGQPLDP 243
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLK--KELKLLSPNELETLFGNIEEIYEFHRDFLDE-----LEERIEeWDDSVER 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  244 MGleTGFLTFGQRFHPYVQYCLRVKQTMAYaREQQETNPLFHAFVQWCEKHKRSGRQMLCDLLIKPHQRITKYPLLLHAV 323
Cdd:smart00325  74 IG--DVFLKLEEFFKIYSEYCSNHPDALEL-LKKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKEL 150

                          170       180
                   ....*....|....*....|....*....
gi 1622843588  324 LKRSPEA-RAQEALNAMIEAVESFLRHVN 351
Cdd:smart00325 151 LKHTPEDhEDREDLKKALKAIKELANQVN 179

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  120 RLPPEDRRHWEIGEG--GDSGLAIEK------SWRELVPghKEMSRELCHQ----QEALWELLTTELIYVRKLKIMTDLL 187
Cdd:COG5422    433 RLEQQARLHLKLMGGlkRNSSLALDKfdeeknLWTLSVP--KEVWESLPKQeikrQEAIYEVIYTERDFVKDLEYLRDTW 510

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  188 AAGLLNlqrvgllTEVSAETlfgNVPSLIRTHRSFWEEVLGPT--LEETRASGQPLDPM--GLETGFLTFGQRFHPYVQY 263
Cdd:COG5422    511 IKPLEE-------SNIIPEN---ARRNFIKHVFANINEIYAVNskLLKALTNRQCLSPIvnGIADIFLDYVPKFEPFIKY 580

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  264 clrVKQTMAYARE---QQETNPLFHAFVQWCEKHKRSGRQMLCDLLIKPHQRITKYPLLLHAVLKRS-PEARAQEALNAM 339
Cdd:COG5422    581 ---GASQPYAKYEferEKSVNPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTdPDNPDTEDIPKV 657

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  340 IEAVESFLRHVNgqvrqgeeQESLAAAAQrigpYEVLEPPSDEVEKNLRPFSTLdltspmlgvaSEHTRQLLLEGPVRVK 419
Cdd:COG5422    658 IDMLREFLSRLN--------FESGKAENR----GDLFHLNQQLLFKPEYVNLGL----------NDEYRKIIFKGVLKRK 715

                          330       340       350       360       370
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1622843588  420 EGR----EGKLDVYLFLFSDVLLVTKP--QRKVDKAKVIRPPLMLEKLVCQPLRD 468
Cdd:COG5422    716 AKSktdgSLRGDIQFFLLDNMLLFCKAkaVNKWRQHKVFQRPIPLELLFISPDED 770

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 410 LLLEGPVRVKEGREGKL--DVYLFLFSDVLLVTKPqRKVDKAKVIRPPLMLEKLVCQPLRD------PHSFLLIHLTefQ 481
Cdd:pfam00169   1 VVKEGWLLKKGGGKKKSwkKRYFVLFDGSLLYYKD-DKSGKSKEPKGSISLSGCEVVEVVAsdspkrKFCFELRTGE--R 77

                          90       100
                  ....*....|....*....|....*.
gi 1622843588 482 CVSSALIVQCPSPTDRARWLEKTQQA 507
Cdd:pfam00169  78 TGKRTYLLQAESEEERKDWIKAIQSA 103

Pleckstrin homology domain-containing family G member 5 and 6 pleckstrin homology (PH) domain; PLEKHG5 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG5 activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in PLEKHG5 are associated with autosomal recessive distal spinal muscular atrophy. PLEKHG6 (also called MyoGEF) has no known function to date. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 408 RQLLLEGPVRVKEGREGKLDVYLFLFSDVLLVTKP-QRKVDKAKVIRPPLMLEKLVCQPLRDPHSFLLIHLTEFQCVSSA 486
Cdd:cd13244     1 RRLLLEGDLRLKEGKGSKVDVHCFLFTDMLLICKPvKRKKDRLKVIRPPYLVDKLVVQELKDPGGFLLVYLNEFHTAVAA 80

                          90       100
                  ....*....|....*....|
gi 1622843588 487 LIVQCPSPTDRARWLEKTQQ 506
Cdd:cd13244    81 YTFQTSSQEDTRRWLDAIRK 100

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  165 ALWELLTTELIYVRKLKIMTDLLAAGLLnlQRVGLLTEVSAETLFGNVPSLIRTHRSFWEEvlgptLEETRA-SGQPLDP 243
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLK--KELKLLSPNELETLFGNIEEIYEFHRDFLDE-----LEERIEeWDDSVER 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588  244 MGleTGFLTFGQRFHPYVQYCLRVKQTMAYaREQQETNPLFHAFVQWCEKHKRSGRQMLCDLLIKPHQRITKYPLLLHAV 323
Cdd:smart00325  74 IG--DVFLKLEEFFKIYSEYCSNHPDALEL-LKKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKEL 150

                          170       180
                   ....*....|....*....|....*....
gi 1622843588  324 LKRSPEA-RAQEALNAMIEAVESFLRHVN 351
Cdd:smart00325 151 LKHTPEDhEDREDLKKALKAIKELANQVN 179

Pleckstrin homology domain-containing family G member 7 pleckstrin homology (PH) domain; PLEKHG7 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG7 is proposed to functions as a guanine nucleotide exchange factor (GEF) and is involved in the regulation of Rho protein signal transduction. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 409 QLLLEGPVRVKEGreGK-LDVYLFLFSDVLLVTKPQRKVDKAK------------------------VIRPPLMLEKLV- 462
Cdd:cd13245     1 QLLHEGPLTLIES--GKtLDVYLFLFDDMLLITKMKKNLKKKKssdsensmpsleltplikeggsytVYKQPIPLDRLCl 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1622843588 463 -------CQPLRDPHSFLLIHLTEFQCVSSALIVQCPSPTDRARWLEKTQ 505
Cdd:cd13245    79 hdvdpneATANGLKHAFVLVHLNRYQQVIGVYTLQASSENTKQTWMSKLR 128

Ephexin Pleckstrin homology (PH) domain; Ephexin-1 (also called NGEF/ neuronal guanine nucleotide exchange factor) plays a role in the homeostatic modulation of presynaptic neurotransmitter release. Specific functions are still unknown for Ephexin-2 (also called RhoGEF19) and Ephexin-3 (also called Rho guanine nucleotide exchange factor 5/RhoGEF5, Transforming immortalized mammary oncogene/p60 TIM, and NGEF/neuronalGEF). Ephexin-4 (also called RhoGEF16) acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. This in turn results in the activation of RhoG which recruits ELMO2 and Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. Ephexin-5 is the specific GEF for RhoA activation and the regulation of vascular smooth muscle contractility. It interacts with EPHA4 PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. The members of the Ephexin family contains a RhoGEF (DH) followed by a PH domain and an SH3 domain. The ephexin PH domain is believed to act with the DH domain in mediating protein-protein interactions. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 406 HTRQLLLEGPVRVKEGREGKL---------DVYLFLFSDVLLVTKP------------QRKVDKAKVIRPPLMLEKLVCq 464
Cdd:cd01221    10 SSRWLVKRGELTELVEDGGSLtfrkkfsktPVYLFLFNDLLLITKKkseerylvldyaPRNLVQVEEVEDPLQLPQPLG- 88

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1622843588 465 plrdPHSFLLIHLTEFQCVSSALIVQCPSPTDRARWLE 502
Cdd:cd01221    89 ----KNLFLLTLLENHEGKTVELLLSAESESDRERWLS 122

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 412 LEGPVRVKEGREGKL--DVYLFLFSDVLLVTKPQRKVDKA--KVIRPPLMLEKLVCQPLRDPHSFLLIHLTEfqcvsSAL 487
Cdd:cd00821     1 KEGYLLKRGGGGLKSwkKRWFVLFEGVLLYYKSKKDSSYKpkGSIPLSGILEVEEVSPKERPHCFELVTPDG-----RTY 75

                          90
                  ....*....|....*
gi 1622843588 488 IVQCPSPTDRARWLE 502
Cdd:cd00821    76 YLQADSEEERQEWLK 90

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 408 RQLLLEGPVrVKEGREGKLDVYLFLFSDVLLVTKPQRKVDKAKVIRpPLMLEKL-VCQPLRDPHSFllihltEFQCVSSA 486
Cdd:cd13389    12 RKLIKEGEL-MKVSRKEMQPRYFFLFNDCLLYTTPVQSSGMLKLNN-ELPLSGMkVKLPEDEEYSN------EFQIISTK 83

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1622843588 487 --LIVQCPSPTDRARWLEKTQQAQITLQKLKA 516
Cdd:cd13389    84 rsFTLIASSEEERDEWVKALSRAIEEHTKKQR 115

Neuroepithelial cell transforming 1 Pleckstrin homology (PH) domain; Net1 (also called ArhGEF8) is part of the family of Rho guanine nucleotide exchange factors. Members of this family activate Rho proteins by catalyzing the exchange of GDP for GTP. The protein encoded by this gene interacts with RhoA within the cell nucleus and may play a role in repairing DNA damage after ionizing radiation. Net1 binds to caspase activation and recruitment domain (CARD)- and membrane-associated guanylate kinase-like domain-containing (CARMA) proteins and regulates nuclear factor kB activation. Net1 contains a RhoGEF domain N-terminal to a single PH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622843588 405 EHTRQLLLEGPVRVKEGREgkldVYLFLFSDVLLVTKPQRKVDKA--KVIRPPLMLEKLVCQPLRD 468
Cdd:cd13224    15 ENSKALLCHGELRNKSGHK----LYVFLFQDILVLTRPVTRNERQsfQVYRQPIPVQELVLEDLQD 76

Intersectin Pleckstrin homology (PH) domain; ITSNs, an adaptor protein family, play a role in endo- and exocytosis, actin cytoskeleton rearrangement and signal transduction. There are two human ITSN genes: ITSN1 and ITSN2. They share significant sequence identity and a similar domain structure having both short and long isoforms produced by alternative splicing. The short isoform (ITSN-S) consists of two Eps15 homology domains (EH1 and EH2), a coiled-coil region (CCR) and five Src homology 3 domains (SH3A-E). The EH domains bind to Asn-Pro-Phe motifs and are implicated in endocytosis and vesicle transport. The SH3 domains bind to proline-rich sequences and are commonly found in proteins implicated in cell signalling pathways, cytoskeletal organization and membrane traffic. The long isoform (ITSN-L) contains three additional C-terminal domains, a Dbl homology domain (DH), a Pleckstrin homology domain (PH) and a C2 domain. The tandem DH-PH domains are present in all Dbl family of GEFs. ITSN acts specifically on Cdc42 through its DH domain with no portion of the PH domain making contact with Cdc42. This is in contrast to Dbs which requires the PH domain for full catalytic activity. The ITSN PH domain binds phosphoinositides. C2 domains are usually involved in Ca2+-dependent and Ca2+-independent phospholipid binding. There are more than 30 proteins that interact with ITSNs. ITSN-S is present in mammals, frogs, flies and nematodes, while ITSN-L is present only in vertebrates. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622843588 408 RQLLLEGP-VRVKEGREgkldVYLFLFSDVLLVTKPQR---------KVDKAKVI-----RPPLMLEKLVCQPLRDPHS- 471
Cdd:cd13264    14 RKFLHSGKlYKAKSNKE----LYGFLFNDFLLLTQPIKplgssgndfVFDNKANIqykmyKTPIFLNEVLVKLPTDPSGd 89

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1622843588 472 ---FLLIHLTEFQCVSSAlivqcpSPTDRARWLEKTQQA 507
Cdd:cd13264    90 epiFHISHIDRVYTLRAE------SINERTAWVQKIKAA 122