Autoregulatory Mechanisms in Protein-tyrosine Kinases
Year: 1998
Type: review
Abstract: Protein-tyrosine kinases (PTKs), 1The abbreviations used are: PTK, protein-tyrosine kinase; RTK, receptor tyrosine kinase; NRTK, non-receptor tyrosine kinase; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SH2, Src homology 2; PTB, phosphotyrosine-binding; pTyr, phosphorylated Tyr; IRS-1, insulin receptor substrate 1; IRK, insulin receptor kinase domain; FGFR1K, FGF receptor 1 kinase domain; IRK0P, unphosphorylated IRK; IRK3P, tris-phosphorylated IRK; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate.1The abbreviations used are: PTK, protein-tyrosine kinase; RTK, receptor tyrosine kinase; NRTK, non-receptor tyrosine kinase; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SH2, Src homology 2; PTB, phosphotyrosine-binding; pTyr, phosphorylated Tyr; IRS-1, insulin receptor substrate 1; IRK, insulin receptor kinase domain; FGFR1K, FGF receptor 1 kinase domain; IRK0P, unphosphorylated IRK; IRK3P, tris-phosphorylated IRK; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate. enzymes that catalyze the transfer of the γ-phosphate of ATP to tyrosine residues of protein substrates, are critical components of signaling pathways that control cellular proliferation and differentiation. PTKs can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs) (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar, 2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar). RTKs span the plasma membrane and contain an extracellular portion, which binds ligand, and an intracellular portion, which possesses catalytic activity and regulatory sequences. The RTK family includes the insulin receptor and the receptors for many growth factors such as epidermal (EGF), platelet-derived (PDGF), fibroblast (FGF), and nerve growth factors (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar). NRTKs contain no extracellular or transmembrane portion but possess modular domains that are responsible for subcellular targeting and regulation of catalytic activity. The NRTK family includes Src, Abl, FAK, and the JAKs among many others (2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar). Because of the key roles PTKs play in cellular signaling processes, their catalytic activity is tightly controlled in normal cells by protein-tyrosine phosphatases, by other protein tyrosine or serine/threonine kinases (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar), and by autoregulatory mechanisms. The recent crystallographic structures of several members of both the RTK and NRTK families, together with extensive biochemical studies, afford an understanding at the molecular level of the autoregulation mechanisms to which PTKs are subject.Receptor Tyrosine KinasesThe RTK family can be broadly divided into two groups depending on the covalent organization of the receptor. Most RTKs possess a single polypeptide chain and are monomeric in the absence of ligand. Members of the insulin receptor subfamily, which includes insulin-like growth factor-1 receptor, are disulfide-linked dimers of two polypeptide chains, forming an α2β2 heterotetramer. Ligand binding to the extracellular portion of RTKs leads to dimerization of monomeric receptors or a rearrangement within the quaternary structure of heterotetrameric receptors, resulting in autophosphorylation of specific tyrosine residues in the cytoplasmic portion (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar).In general, tyrosine autophosphorylation either stimulates the intrinsic catalytic (kinase) activity of the receptor or generates recruitment sites for downstream signaling proteins containing phosphotyrosine-recognition domains, such as the Src homology 2 (SH2) domain or the phosphotyrosine-binding (PTB) domain (3Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The vast majority of PTKs contain and in the kinase which and of the protein kinase catalytic T. Scopus Google Scholar). of to be critical for of catalytic activity and for RTKs such as the insulin receptor Cell. Full Text PDF PubMed Scopus Google Scholar), FGF receptor A. Schlessinger J. Cell. PubMed Scopus Google Scholar), growth receptor A. Google Scholar), and nerve growth receptor G. Google Scholar), and for NRTKs such as Src Cell. Full Text PDF PubMed Scopus Google Scholar), T. T. J. 1995; PubMed Scopus Google Scholar), and J. T. Cell. 17: PubMed Scopus Google of protein by RTKs of receptor catalytic activity but of protein to the receptor a a autophosphorylation of in FGF receptor 1 a binding for the domain of The of the domain with phosphorylated is critical for the and of by FGF receptor 1 T. Schlessinger J. Nature. PubMed Scopus Google Scholar). the domain of insulin receptor substrate 1 is to of the insulin receptor, the homology domain to to the plasma membrane J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of to to the insulin receptor, of in structures of the unphosphorylated of the insulin receptor kinase domain Nature. PubMed Scopus Google and the FGF receptor 1 kinase domain Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google on the molecular mechanisms by which RTKs are in a activity to autophosphorylation of the of the in the kinase is in the in to be 1 of the protein at the of the is in to J. PubMed Scopus Google Scholar, J. PubMed Scopus Google in the of the to with ATP are with autophosphorylation of a J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). of with in the insulin receptor in an of of kinase activity Cell. Full Text PDF PubMed Scopus Google Scholar), with an for the that to with protein chain and other for binding in the but is of that binding of and the of the insulin receptor and are the as in the structure a that in Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). FGFR1K, of the two and in is in the the at the of the in and residues are to with binding of protein 1 Because of the in of the the the ATP binding in is and ATP can be into and to in be to the that which is a in and an in to that a at the polypeptide chain to the ATP binding the and of the kinase 1 structures of tris-phosphorylated J. PubMed Scopus Google and Nature. PubMed Scopus Google a molecular for understanding autophosphorylation of stimulates catalytic activity. of the in the in a in the of the of both and J. PubMed Scopus Google Scholar, Nature. PubMed Scopus Google Scholar). The of the phosphorylated to the binding sites for ATP and protein and the of residues in the protein and the and in and the of the in is of for the kinase domain of The kinase domains of the insulin and insulin-like growth factor-1 receptors are within and to the of for monomeric RTKs in the absence of ligand, within the of the plasma membrane receptor be to in an of autophosphorylation and The insulin receptor can be in the absence of by tyrosine such as which can of the of insulin G. A. J. Full Text PDF PubMed Google Scholar, 1995; PubMed Google Scholar), that is to RTKs is the crystallographic factors that of the unphosphorylated and are and an of the in of be with substrate and in and for binding with the of in the the a that substrate that the for a RTK to to of or other in the absence of to of receptors that in the of RTKs in of an the in and in with and A. 1995; PubMed Scopus Google G. T. PubMed Scopus Google Scholar). FGF receptor a of for the in the a of 1995; PubMed Scopus Google Scholar), a with of receptors are in cells in the absence of J. PubMed Scopus Google Scholar, Cell. PubMed Scopus Google Scholar). the the of a such as to receptor the of a of the receptor extracellular The recent structure of growth to domain 2 of receptor an G. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The structure a of growth which is a disulfide-linked and two of is the of the cytoplasmic domains in the receptor a cytoplasmic is autophosphorylation of at sites to dimers within dimers of Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The of a cytoplasmic be to a of the a tyrosine in the is the receptor subfamily, of with no on receptor kinase activity or signaling A. PubMed Scopus Google Scholar). of kinase activity binding of a cytoplasmic in which the are in a for the cytoplasmic domains of the receptor the two cytoplasmic domains as substrate and for The in the by receptor dimerization to kinases insulin is the insulin receptor, the kinase activity of the receptor is A. PubMed Scopus Google Scholar), that autophosphorylation a of the cytoplasmic domains is to for of tyrosine kinase activity by receptor The of RTKs is and majority of with protein substrate binding and ATP of are with substrate and the absence of ligand, the of receptors is of to the extracellular domain receptor to of the the the which substrate binding and the of residues in on which as binding sites for downstream signaling Tyrosine to a tyrosine kinase NRTKs contain within the polypeptide chain several or such as SH2, and homology a and a Src an domain by an a kinase and a be extracellular to the of NRTKs by both and studies, as as an of Src that Src of domain with a to the kinase domain 1990; PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar), which is phosphorylated by the NRTK A. Nature. PubMed Scopus Google Scholar). The domain to be in regulation of catalytic activity and (2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar), but the by which The recent structures of Src Nature. PubMed Scopus Google Scholar, A. A. Courtneidge S.A. G. J. PubMed Scopus Google and J. Nature. PubMed Scopus Google the roles of the and domains in the autoregulation of Src family the structures of Src and the domain with in the as by to kinase activity the on the of the of the the The in the structures is the of the domain with a portion of the that the domain to the kinase domain domains are to to proteins containing that PubMed Scopus Google Scholar). the of Src family members such as and a is for other family members Src and the is and an the domain and the the absence of the in Src, portion of the a to which the domain and of of Src on the structure Nature. PubMed Scopus Google Scholar). the kinase domain of Src is in an two the binding of the domain to and the binding of the domain to the which a a of extracellular the kinase activity of Src can be by binding of the domain to binding of the domain to or of Full of Src autophosphorylation of in the the and domains kinase in the of protein kinases an in that in kinases an with an in Nature. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). the Src and the and is The of is by the kinase and the in is by the domain Nature. PubMed Scopus Google Scholar, A. A. Courtneidge S.A. G. J. PubMed Scopus Google Scholar, J. Nature. PubMed Scopus Google Scholar). of kinase activity is to the of as as a of the the and of the which and to ATP and is in to growth factors such as PDGF, which receptor dimerization and autophosphorylation of autophosphorylation in the of the receptor can the domain of Src with A. Courtneidge S.A. J. PubMed Scopus Google Scholar, G. Courtneidge S.A. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), with the of Src in the of the Src domain to of the receptor leads to of Src kinase activity by the on the kinase domain Src can be by proteins containing that with the for binding to the domain (2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar, J. Nature. PubMed Scopus Google Scholar), which in of the the Src on a tyrosine in the which the Nature. PubMed Scopus Google of the family of NRTKs and are to the cytoplasmic domain of receptors of a to the extracellular domain of receptor leads to receptor dimerization and the of two JAKs be family PubMed Scopus Google Scholar). The of of JAKs by to be to that of RTKs by their specific both receptor dimerization the of catalytic domains, which are either intrinsic (RTKs) or of to an kinase by tyrosine the structures of the catalytic domains of the insulin receptor, FGF receptor, and and the structures of Src and a of the mechanisms by which tyrosine kinase activity is an understanding of tyrosine autophosphorylation stimulates catalytic activity and of the domains of the Src family PTKs to catalytic activity. the structures of PTKs in with G. Schlessinger J. PubMed Scopus Google to the of and specific for the of such as in which activity of PTKs A. A. 1995; PubMed Scopus Google Scholar). and of other receptor and non-receptor PTKs other autoregulatory mechanisms to which of enzymes is Protein-tyrosine kinases (PTKs), 1The abbreviations used are: PTK, protein-tyrosine kinase; RTK, receptor tyrosine kinase; NRTK, non-receptor tyrosine kinase; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SH2, Src homology 2; PTB, phosphotyrosine-binding; pTyr, phosphorylated Tyr; IRS-1, insulin receptor substrate 1; IRK, insulin receptor kinase domain; FGFR1K, FGF receptor 1 kinase domain; IRK0P, unphosphorylated IRK; IRK3P, tris-phosphorylated IRK; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate.1The abbreviations used are: PTK, protein-tyrosine kinase; RTK, receptor tyrosine kinase; NRTK, non-receptor tyrosine kinase; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; SH2, Src homology 2; PTB, phosphotyrosine-binding; pTyr, phosphorylated Tyr; IRS-1, insulin receptor substrate 1; IRK, insulin receptor kinase domain; FGFR1K, FGF receptor 1 kinase domain; IRK0P, unphosphorylated IRK; IRK3P, tris-phosphorylated IRK; AMP-PNP, adenosine 5′-(β,γ-imino)triphosphate. enzymes that catalyze the transfer of the γ-phosphate of ATP to tyrosine residues of protein substrates, are critical components of signaling pathways that control cellular proliferation and differentiation. PTKs can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs) (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar, 2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar). RTKs span the plasma membrane and contain an extracellular portion, which binds ligand, and an intracellular portion, which possesses catalytic activity and regulatory sequences. The RTK family includes the insulin receptor and the receptors for many growth factors such as epidermal (EGF), platelet-derived (PDGF), fibroblast (FGF), and nerve growth factors (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar). NRTKs contain no extracellular or transmembrane portion but possess modular domains that are responsible for subcellular targeting and regulation of catalytic activity. The NRTK family includes Src, Abl, FAK, and the JAKs among many others (2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar). Because of the key roles PTKs play in cellular signaling processes, their catalytic activity is tightly controlled in normal cells by protein-tyrosine phosphatases, by other protein tyrosine or serine/threonine kinases (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar), and by autoregulatory mechanisms. The recent crystallographic structures of several members of both the RTK and NRTK families, together with extensive biochemical studies, afford an understanding at the molecular level of the autoregulation mechanisms to which PTKs are Tyrosine KinasesThe RTK family can be broadly divided into two groups depending on the covalent organization of the receptor. Most RTKs possess a single polypeptide chain and are monomeric in the absence of ligand. Members of the insulin receptor subfamily, which includes insulin-like growth factor-1 receptor, are disulfide-linked dimers of two polypeptide chains, forming an α2β2 heterotetramer. Ligand binding to the extracellular portion of RTKs leads to dimerization of monomeric receptors or a rearrangement within the quaternary structure of heterotetrameric receptors, resulting in autophosphorylation of specific tyrosine residues in the cytoplasmic portion (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar).In general, tyrosine autophosphorylation either stimulates the intrinsic catalytic (kinase) activity of the receptor or generates recruitment sites for downstream signaling proteins containing phosphotyrosine-recognition domains, such as the Src homology 2 (SH2) domain or the phosphotyrosine-binding (PTB) domain (3Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The vast majority of PTKs contain and in the kinase which and of the protein kinase catalytic T. Scopus Google Scholar). of to be critical for of catalytic activity and for RTKs such as the insulin receptor Cell. Full Text PDF PubMed Scopus Google Scholar), FGF receptor A. Schlessinger J. Cell. PubMed Scopus Google Scholar), growth receptor A. Google Scholar), and nerve growth receptor G. Google Scholar), and for NRTKs such as Src Cell. Full Text PDF PubMed Scopus Google Scholar), T. T. J. 1995; PubMed Scopus Google Scholar), and J. T. Cell. 17: PubMed Scopus Google of protein by RTKs of receptor catalytic activity but of protein to the receptor a a autophosphorylation of in FGF receptor 1 a binding for the domain of The of the domain with phosphorylated is critical for the and of by FGF receptor 1 T. Schlessinger J. Nature. PubMed Scopus Google Scholar). the domain of insulin receptor substrate 1 is to of the insulin receptor, the homology domain to to the plasma membrane J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of to to the insulin receptor, of in The RTK family can be broadly divided into two groups depending on the covalent organization of the receptor. Most RTKs possess a single polypeptide chain and are monomeric in the absence of ligand. Members of the insulin receptor subfamily, which includes insulin-like growth factor-1 receptor, are disulfide-linked dimers of two polypeptide chains, forming an α2β2 heterotetramer. Ligand binding to the extracellular portion of RTKs leads to dimerization of monomeric receptors or a rearrangement within the quaternary structure of heterotetrameric receptors, resulting in autophosphorylation of specific tyrosine residues in the cytoplasmic portion (1Ullrich A. Schlessinger J. Cell. 1990; 61: 203-212Abstract Full Text PDF PubMed Scopus (4581) Google Scholar). general, tyrosine autophosphorylation either stimulates the intrinsic catalytic (kinase) activity of the receptor or generates recruitment sites for downstream signaling proteins containing phosphotyrosine-recognition domains, such as the Src homology 2 (SH2) domain or the phosphotyrosine-binding (PTB) domain (3Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The vast majority of PTKs contain and in the kinase which and of the protein kinase catalytic T. Scopus Google Scholar). of to be critical for of catalytic activity and for RTKs such as the insulin receptor Cell. Full Text PDF PubMed Scopus Google Scholar), FGF receptor A. Schlessinger J. Cell. PubMed Scopus Google Scholar), growth receptor A. Google Scholar), and nerve growth receptor G. Google Scholar), and for NRTKs such as Src Cell. Full Text PDF PubMed Scopus Google Scholar), T. T. J. 1995; PubMed Scopus Google Scholar), and J. T. Cell. 17: PubMed Scopus Google Scholar). of protein by RTKs of receptor catalytic activity but of protein to the receptor a a autophosphorylation of in FGF receptor 1 a binding for the domain of The of the domain with phosphorylated is critical for the and of by FGF receptor 1 T. Schlessinger J. Nature. PubMed Scopus Google Scholar). the domain of insulin receptor substrate 1 is to of the insulin receptor, the homology domain to to the plasma membrane J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of to to the insulin receptor, of in structures of the unphosphorylated of the insulin receptor kinase domain Nature. PubMed Scopus Google and the FGF receptor 1 kinase domain Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google on the molecular mechanisms by which RTKs are in a activity to autophosphorylation of the of the in the kinase is in the in to be 1 of the protein at the of the is in to J. PubMed Scopus Google Scholar, J. PubMed Scopus Google in the of the to with ATP are with autophosphorylation of a J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). of with in the insulin receptor in an of of kinase activity Cell. Full Text PDF PubMed Scopus Google Scholar), with an for the that to with protein chain and other for binding in the but is of that binding of and the of the insulin receptor and are the as in the structure a that in Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). FGFR1K, of the two and in is in the the at the of the in and residues are to with binding of protein 1 Because of the in of the the the ATP binding in is and ATP can be into and to in be to the that which is a in and an in to that a at the polypeptide chain to the ATP binding the and of the kinase 1 structures of tris-phosphorylated J. PubMed Scopus Google and Nature. PubMed Scopus Google a molecular for understanding autophosphorylation of stimulates catalytic activity. of the in the in a in the of the of both and J. PubMed Scopus Google Scholar, Nature. PubMed Scopus Google Scholar). The of the phosphorylated to the binding sites for ATP and protein and the of residues in the protein and the and in and the of the in is of for the kinase domain of The kinase domains of the insulin and insulin-like growth factor-1 receptors are within and to the of for monomeric RTKs in the absence of ligand, within the of the plasma membrane receptor be to in an of autophosphorylation and The insulin receptor can be in the absence of by tyrosine such as which can of the of insulin G. A. J. Full Text PDF PubMed Google Scholar, 1995; PubMed Google Scholar), that is to RTKs is the crystallographic factors that of the unphosphorylated and are and an of the in of be with substrate and in and for binding with the of in the the a that substrate that the for a RTK to to of or other in the absence of to of receptors that in the of RTKs in of an the in and in with and A. 1995; PubMed Scopus Google G. T. PubMed Scopus Google Scholar). FGF receptor a of for the in the a of 1995; PubMed Scopus Google Scholar), a with of receptors are in cells in the absence of J. PubMed Scopus Google Scholar, Cell. PubMed Scopus Google Scholar). the the structures of the unphosphorylated of the insulin receptor kinase domain Nature. PubMed Scopus Google and the FGF receptor 1 kinase domain Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google on the molecular mechanisms by which RTKs are in a activity to autophosphorylation of the of the in the kinase is in the in to be 1 of the protein at the of the is in to J. PubMed Scopus Google Scholar, J. PubMed Scopus Google in the of the to with ATP are with autophosphorylation of a J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). of with in the insulin receptor in an of of kinase activity Cell. Full Text PDF PubMed Scopus Google Scholar), with an for the that to with protein chain and other for binding in the but is of that binding of and the of the insulin receptor and are the as in the structure a that in Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). FGFR1K, of the two and in is in the the at the of the in and residues are to with binding of protein 1 Because of the in of the the the ATP binding in is and ATP can be into and to in be to the that which is a in and an in to that a at the polypeptide chain to the ATP binding the and of the kinase 1 The structures of tris-phosphorylated J. PubMed Scopus Google and Nature. PubMed Scopus Google a molecular for understanding autophosphorylation of stimulates catalytic activity. of the in the in a in the of the of both and J. PubMed Scopus Google Scholar, Nature. PubMed Scopus Google Scholar). The of the phosphorylated to the binding sites for ATP and protein and the of residues in the protein and the and in and the of the in is of for the kinase domain of The kinase domains of the insulin and insulin-like growth factor-1 receptors are within and to the of for monomeric RTKs in the absence of ligand, within the of the plasma membrane receptor be to in an of autophosphorylation and The insulin receptor can be in the absence of by tyrosine such as which can of the of insulin G. A. J. Full Text PDF PubMed Google Scholar, 1995; PubMed Google Scholar), that is to RTKs is the crystallographic factors that of the unphosphorylated and are and an of the in of be with substrate and in and for binding with the of in the the a that substrate that the for a RTK to to of or other in the absence of to of receptors that in the of RTKs in of an the in and in with and A. 1995; PubMed Scopus Google G. T. PubMed Scopus Google Scholar). FGF receptor a of for the in the a of 1995; PubMed Scopus Google Scholar), a with of receptors are in cells in the absence of J. PubMed Scopus Google Scholar, Cell. PubMed Scopus Google Scholar). the the of a such as to receptor the of a of the receptor extracellular The recent structure of growth to domain 2 of receptor an G. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The structure a of growth which is a disulfide-linked and two of is the of the cytoplasmic domains in the receptor a cytoplasmic is autophosphorylation of at sites to dimers within dimers of Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The of a cytoplasmic be to a of the a tyrosine in the is the receptor subfamily, of with no on receptor kinase activity or signaling A. PubMed Scopus Google Scholar). of kinase activity binding of a cytoplasmic in which the are in a for the cytoplasmic domains of the receptor the two cytoplasmic domains as substrate and for The in the by receptor dimerization to kinases insulin is the insulin receptor, the kinase activity of the receptor is A. PubMed Scopus Google Scholar), that autophosphorylation a of the cytoplasmic domains is to activity. of a such as to receptor the of a of the receptor extracellular The recent structure of growth to domain 2 of receptor an G. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The structure a of growth which is a disulfide-linked and two of is the of the cytoplasmic domains in the receptor a cytoplasmic is autophosphorylation of at sites to dimers within dimers of Schlessinger J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The of a cytoplasmic be to a of the a tyrosine in the is the receptor subfamily, of with no on receptor kinase activity or signaling A. PubMed Scopus Google Scholar). of kinase activity binding of a cytoplasmic in which the are in a for the cytoplasmic domains of the receptor the two cytoplasmic domains as substrate and for The in the by receptor dimerization to kinases insulin is the insulin receptor, the kinase activity of the receptor is A. PubMed Scopus Google Scholar), that autophosphorylation a of the cytoplasmic domains is to activity. Tyrosine to a tyrosine kinase NRTKs contain within the polypeptide chain several or such as SH2, and homology a and a Src an domain by an a kinase and a be extracellular to the of NRTKs by both and studies, as as an of Src that Src of domain with a to the kinase domain 1990; PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar), which is phosphorylated by the NRTK A. Nature. PubMed Scopus Google Scholar). The domain to be in regulation of catalytic activity and (2Superti-Furga G. Courtneidge S.A. Bioessays. 1995; 17: 321-330Crossref PubMed Scopus (178) Google Scholar), but the by which The recent structures of Src Nature. PubMed Scopus Google Scholar, A. A. Courtneidge S.A. G. J. PubMed Scopus Google and J. Nature. PubMed Scopus Google the roles of the and domains in the autoregulation of Src family the structures of Src and the domain with in the as by to kinase activity the on the of the of the the The in the structures is the of the domain with a portion of the that the domain to the kinase domain domains are to to proteins containing that PubMed Scopus Google Scholar). the of Src family members such as and a is for other family members Src and the is and an the domain and the the absence of the in Src, portion of the a to which the domain the and domains kinase in the of protein kinases an in that in kinases an with an in Nature. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). the Src and the and is The of is by the kinase and the in is by the domain Nature. PubMed Scopus Google Scholar, A. A. Courtneidge S.A. G. J. PubMed Scopus Google Scholar, J. Nature. PubMed Scopus Google Scholar). of kinase activity is to the of as as a of the the and of the which and to ATP and is in
Source: Journal of Biological Chemistry
Institutions: NYU Langone Health, New York University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
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