Growth factor receptor domain IV; This is the fourth extracellular domain of receptor tyrosine protein kinases. Interaction between this domain and the furin-like domain (pfam00757) regulates the binding of ligands to the receptor L domains (pfam01030).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574 511 CHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHY 590
Cdd:pfam14843   2 CDPLCSSEGCWGPGPDQCLSCRNFSRGGTCVESCNILQGEPREYVVNSTCVPCHPECLPQNGTATCSGPGADNCTKCAHF 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1844139574 591 KDPPFCVARCPSGVKPDLSymPIWKFPDEEGACQPCPINCTHSCVDLDDKGCP 643
Cdd:pfam14843  82 RDGPHCVSSCPSGVLGEND--LIWKYADANGVCQPCHPNCTQGCTGPGLTGCP 132

Receptor L domain; The L domains from these receptors make up the bilobal ligand binding site. Each L domain consists of a single-stranded right hand beta-helix. This Pfam entry is missing the first 50 amino acid residues of the domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574  52 GCQVVQGNLELTYLPTN---ASLSFLQDIQEVQGYVLIAH-NQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDplnntt 127
Cdd:pfam01030   1 NCTVIYGNLEITLIDENndsELLSFLSNVEEITGYLLIANtNLVSLSFLPNLRIIRGRNLFDDNYALYILDNPN------ 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1844139574 128 pvtgaspggLRELQLRSLTEILKGGVLIQRNPQLCYQDT-ILWKDIF 173
Cdd:pfam01030  75 ---------LTELGLPSLKEITSGGVYIHNNPKLCYTETeILWKLLL 112

Protein Kinases, catalytic domain; The protein kinase superfamily is mainly composed of the catalytic domains of serine/threonine-specific and tyrosine-specific protein kinases. It also includes RIO kinases, which are atypical serine protein kinases, aminoglycoside phosphotransferases, and choline kinases. These proteins catalyze the transfer of the gamma-phosphoryl group from ATP to hydroxyl groups in specific substrates such as serine, threonine, or tyrosine residues of proteins.

                          10        20
                  ....*....|....*....|....*
gi 1844139574 712 MRILKETELRKVKVLGSGAFGTVYK 736
Cdd:cd05057     1 LRIVKETELEKGKVLGSGAFGTVYK 25

Growth factor receptor domain IV; This is the fourth extracellular domain of receptor tyrosine protein kinases. Interaction between this domain and the furin-like domain (pfam00757) regulates the binding of ligands to the receptor L domains (pfam01030).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574 511 CHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHY 590
Cdd:pfam14843   2 CDPLCSSEGCWGPGPDQCLSCRNFSRGGTCVESCNILQGEPREYVVNSTCVPCHPECLPQNGTATCSGPGADNCTKCAHF 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1844139574 591 KDPPFCVARCPSGVKPDLSymPIWKFPDEEGACQPCPINCTHSCVDLDDKGCP 643
Cdd:pfam14843  82 RDGPHCVSSCPSGVLGEND--LIWKYADANGVCQPCHPNCTQGCTGPGLTGCP 132

Receptor L domain; The L domains from these receptors make up the bilobal ligand binding site. Each L domain consists of a single-stranded right hand beta-helix. This Pfam entry is missing the first 50 amino acid residues of the domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574  52 GCQVVQGNLELTYLPTN---ASLSFLQDIQEVQGYVLIAH-NQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDplnntt 127
Cdd:pfam01030   1 NCTVIYGNLEITLIDENndsELLSFLSNVEEITGYLLIANtNLVSLSFLPNLRIIRGRNLFDDNYALYILDNPN------ 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1844139574 128 pvtgaspggLRELQLRSLTEILKGGVLIQRNPQLCYQDT-ILWKDIF 173
Cdd:pfam01030  75 ---------LTELGLPSLKEITSGGVYIHNNPKLCYTETeILWKLLL 112

Catalytic domain of Epidermal Growth Factor Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER, ErbB) subfamily members include EGFR (HER1, ErbB1), HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), and similar proteins. They are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other PTKs, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, resulting in the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Collectively, they can recognize a variety of ligands including EGF, TGFalpha, and neuregulins, among others. All four subfamily members can form homo- or heterodimers. HER3 contains an impaired kinase domain and depends on its heterodimerization partner for activation. EGFR subfamily members are involved in signaling pathways leading to a broad range of cellular responses including cell proliferation, differentiation, migration, growth inhibition, and apoptosis. Gain of function alterations, through their overexpression, deletions, or point mutations in their kinase domains, have been implicated in various cancers. These receptors are targets of many small molecule inhibitors and monoclonal antibodies used in cancer therapy. The EGFR subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20
                  ....*....|....*....|....*
gi 1844139574 712 MRILKETELRKVKVLGSGAFGTVYK 736
Cdd:cd05057     1 LRIVKETELEKGKVLGSGAFGTVYK 25

Furin-like repeats;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1844139574  557 ARHCLPCHPECQpqngsvTCFGPEADQCVACAH--YKDPPFCVARCPSG 603
Cdd:smart00261   1 DGECKPCHPECA------TCTGPGPDDCTSCKHgfFLDGGKCVSECPPG 43

Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1844139574 562 PCHPECQpqngsvTCFGPEADQCVACAH--YKDPPFCVARCPSGVKPD 607
Cdd:cd00064     1 PCHPSCA------TCTGPGPDQCTSCRHgfYLDGGTCVSECPEGTYAD 42

Growth factor receptor domain IV; This is the fourth extracellular domain of receptor tyrosine protein kinases. Interaction between this domain and the furin-like domain (pfam00757) regulates the binding of ligands to the receptor L domains (pfam01030).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574 511 CHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHY 590
Cdd:pfam14843   2 CDPLCSSEGCWGPGPDQCLSCRNFSRGGTCVESCNILQGEPREYVVNSTCVPCHPECLPQNGTATCSGPGADNCTKCAHF 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1844139574 591 KDPPFCVARCPSGVKPDLSymPIWKFPDEEGACQPCPINCTHSCVDLDDKGCP 643
Cdd:pfam14843  82 RDGPHCVSSCPSGVLGEND--LIWKYADANGVCQPCHPNCTQGCTGPGLTGCP 132

Receptor L domain; The L domains from these receptors make up the bilobal ligand binding site. Each L domain consists of a single-stranded right hand beta-helix. This Pfam entry is missing the first 50 amino acid residues of the domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574  52 GCQVVQGNLELTYLPTN---ASLSFLQDIQEVQGYVLIAH-NQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDplnntt 127
Cdd:pfam01030   1 NCTVIYGNLEITLIDENndsELLSFLSNVEEITGYLLIANtNLVSLSFLPNLRIIRGRNLFDDNYALYILDNPN------ 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1844139574 128 pvtgaspggLRELQLRSLTEILKGGVLIQRNPQLCYQDT-ILWKDIF 173
Cdd:pfam01030  75 ---------LTELGLPSLKEITSGGVYIHNNPKLCYTETeILWKLLL 112

Catalytic domain of Epidermal Growth Factor Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER, ErbB) subfamily members include EGFR (HER1, ErbB1), HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), and similar proteins. They are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other PTKs, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, resulting in the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Collectively, they can recognize a variety of ligands including EGF, TGFalpha, and neuregulins, among others. All four subfamily members can form homo- or heterodimers. HER3 contains an impaired kinase domain and depends on its heterodimerization partner for activation. EGFR subfamily members are involved in signaling pathways leading to a broad range of cellular responses including cell proliferation, differentiation, migration, growth inhibition, and apoptosis. Gain of function alterations, through their overexpression, deletions, or point mutations in their kinase domains, have been implicated in various cancers. These receptors are targets of many small molecule inhibitors and monoclonal antibodies used in cancer therapy. The EGFR subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20
                  ....*....|....*....|....*
gi 1844139574 712 MRILKETELRKVKVLGSGAFGTVYK 736
Cdd:cd05057     1 LRIVKETELEKGKVLGSGAFGTVYK 25

Catalytic domain of the Protein Tyrosine Kinase, HER2; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. HER2 (ErbB2, HER2/neu) is a member of the EGFR (HER, ErbB) subfamily of proteins, which are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other PTKs, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. HER2 does not bind to any known EGFR subfamily ligands, but contributes to the kinase activity of all possible heterodimers. It acts as the preferred partner of other ligand-bound EGFR proteins and functions as a signal amplifier, with the HER2-HER3 heterodimer being the most potent pair in mitogenic signaling. HER2 plays an important role in cell development, proliferation, survival and motility. Overexpression of HER2 results in its activation and downstream signaling, even in the absence of ligand. HER2 overexpression, mainly due to gene amplification, has been shown in a variety of human cancers. Its role in breast cancer is especially well-documented. HER2 is up-regulated in about 25% of breast tumors and is associated with increases in tumor aggressiveness, recurrence and mortality. HER2 is a target for monoclonal antibodies and small molecule inhibitors, which are being developed as treatments for cancer. The first humanized antibody approved for clinical use is Trastuzumab (Herceptin), which is being used in combination with other therapies to improve the survival rates of patients with HER2-overexpressing breast cancer. The HER2 subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20
                  ....*....|....*....|....*
gi 1844139574 712 MRILKETELRKVKVLGSGAFGTVYK 736
Cdd:cd05109     1 MRILKETELKKVKVLGSGAFGTVYK 25

Transmembrane domain of ErbB2, a Protein Tyrosine Kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. ErbB2 (HER2, HER2/neu) is a member of the EGFR (HER, ErbB) subfamily of proteins, which are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane (TM) helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. It is activated by ligand-induced dimerization, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. ErbB2 does not bind to any known EGFR subfamily ligands, but contributes to the kinase activity of all possible heterodimers. It acts as the preferred partner of other ligand-bound EGFR proteins and functions as a signal amplifier, with the ErbB2-ErbB3 heterodimer being the most potent pair in mitogenic signaling. The TM domain not only serves as a membrane anchor, but also plays an important role in receptor dimerization and optimal activation. Mutations in the TM domain of ErbB2 have been associated with increased breast cancer risk. ErbB2 plays an important role in cell development, proliferation, survival and motility. Overexpression of ErbB2 results in its activation and downstream signaling, even in the absence of ligand. ErbB2 overexpression, mainly due to gene amplification, has been shown in a variety of human cancers. Its role in breast cancer is especially well-documented. ErbB2 is up-regulated in about 25% of breast tumors and is associated with increases in tumor aggressiveness, recurrence and mortality. ErbB2 is a target for monoclonal antibodies and small molecule inhibitors, which are being developed as treatments for cancer. The first humanized antibody approved for clinical use is Trastuzumab (Herceptin), which is being used in combination with other therapies to improve the survival rates of patients with HER2-overexpressing breast cancer.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1844139574 641 GCPAEQRASPLTSIISAVVGILLVVVLGVVFGILIKRRQQKIRK 684
Cdd:cd12094     1 GCPAEQRASPLTSIIAGVVGILLVVVLLVVFGILIKRRRQKIRK 44

Catalytic domain of the Protein Tyrosine Kinase, HER4; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. HER4 (ErbB4) is a member of the EGFR (HER, ErbB) subfamily of proteins, which are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other PTKs, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, leading to the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Ligands that bind HER4 fall into two groups, the neuregulins (or heregulins) and some EGFR (HER1) ligands including betacellulin, HBEGF, and epiregulin. All four neuregulins (NRG1-4) interact with HER4. Upon ligand binding, HER4 forms homo- or heterodimers with other HER proteins. HER4 is essential in embryonic development. It is implicated in mammary gland, cardiac, and neural development. As a postsynaptic receptor of NRG1, HER4 plays an important role in synaptic plasticity and maturation. The impairment of NRG1/HER4 signaling may contribute to schizophrenia. The HER4 subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1844139574 712 MRILKETELRKVKVLGSGAFGTVYKsgggdltlGLEPSEEEAPRSPLA 759
Cdd:cd05110     1 LRILKETELKRVKVLGSGAFGTVYK--------GIWVPEGETVKIPVA 40

Furin-like repeats. Cysteine rich region. Exact function of the domain is not known. Furin is a serine-kinase dependent proprotein processor. Other members of this family include endoproteases and cell surface receptors.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1844139574 562 PCHPECQpqngsvTCFGPEADQCVACAH--YKDPPFCVARCPSGVKPD 607
Cdd:cd00064     1 PCHPSCA------TCTGPGPDQCTSCRHgfYLDGGTCVSECPEGTYAD 42

Growth factor receptor domain IV; This is the fourth extracellular domain of receptor tyrosine protein kinases. Interaction between this domain and the furin-like domain (pfam00757) regulates the binding of ligands to the receptor L domains (pfam01030).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574 194 PCSPMCKGSRCWGESSEDCQS----LTRTVCAGGCARCKGP-----LPTDC--CHEQCA-----AGCTGPKHSDCLACLH 257
Cdd:pfam14843   1 VCDPLCSSEGCWGPGPDQCLScrnfSRGGTCVESCNILQGEpreyvVNSTCvpCHPECLpqngtATCSGPGADNCTKCAH 80

                          90
                  ....*....|...
gi 1844139574 258 FNHSGICELHCPA 270
Cdd:pfam14843  81 FRDGPHCVSSCPS 93

Furin-like repeats;

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1844139574  509 LACHQLCArgHCWGPGPTQCVNCSQ--FLRGQECVEEC 544
Cdd:smart00261   5 KPCHPECA--TCTGPGPDDCTSCKHgfFLDGGKCVSEC 40

Furin-like cysteine rich region;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1844139574 504 CVGEGLACHQLCArGHCWGPGPTQCVNCSQFLRGQECVEECRvlqglPREYVNARHCLPcHPECqPQNGSVTCFgpeadq 583
Cdd:pfam00757  42 CTKPGECCHEQCL-GGCTGPNDSDCLACRHFNDEGTCVDQCP-----PGTYQFGWRCVT-FKEC-PKSHLPGYN------ 107

                          90       100
                  ....*....|....*....|
gi 1844139574 584 cvacAHYKDPPFCVARCPSG 603
Cdd:pfam00757 108 ----PLVIHNGECVRECPSG 123