The Protein Kinase Complement of the Human Genome

Manning, Gerard; Whyte, David B.; Martinez, Robert A.; Hunter, Tony; Sudarsanam, Sucha

doi:10.1126/science.1075762

Cited by 7,242 publications

(6,624 citation statements)

References 35 publications

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“…These are followed by a single-pass transmembrane domain, and a catalytically competent, cytoplasmic PTK (FIG.1). The TAM receptors are most closely related to RON (also known as CD136, MST1R), the PTK receptor for macrophagestimulating protein, and to MET, the hepatocyte growth-factor receptor 1 . Similar to all other receptor PTKs, the TAMs seem to signal as dimers 7 (FIG.…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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“…Multiple-Sequence Comparison by Log Expectation (MUSCLE)52 was used to align the mutated kinase domain of PRKD1 against an alignment of the eukaryotic protein kinase (ePK) domains used in Manning et al 53 describing the major kinase groups. All sequences observed to display a glutamic acid or aspartic acid at the homologous site of the PRKD1 alteration were identified and used in conjunction with Kinome-render54 to annotate the tree shown in Cell lines.…”

Section: Homology Modelingmentioning

confidence: 99%

Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands

Weinreb¹,

Piscuoglio²,

Martelotto³

et al. 2014

Nat Genet

195

212

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“…1 Key to the initiation and progression of cancer is the sustained activation of tyrosine kinase signaling pathways, which relay signals for growth, survival, migration and differentiation. 2 Receptor tyrosine kinases (RTKs) constitute a family of receptors that include epidermal growth factor receptor (EGFR), insulin receptor (IR) and insulin-like growth factor receptor (IGF1R). Either through mutation or upon extracellular ligand binding, they activate downstream signaling pathways, including Ras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K) pathways.…”

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confidence: 99%

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

Vanderlaag¹,

Wang²,

Fayadat‐Dilman³

et al. 2011

Intl Journal of Cancer

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Regenerating islet‐derived family member, 4 (Reg IV) is a secreted protein and member of the C‐type lectin superfamily. Expression analyses have characterized Reg IV as a prognostic marker for certain cancers; however, the functional role of Reg IV in cancer, including downstream signaling, has only begun to be elucidated. To investigate the biological role of Reg IV in cancer, phosphorylation events were studied in cancer cell lines in the context of either Reg IV stimulation (HCT116 cells) or knockdown of endogenous Reg IV (PC3 and KM12 cells). In addition to the previously observed impact on epidermal growth factor receptor and Akt phosphorylation, we observed modulation in the phosphorylation of multiple additional receptor tyrosine kinases (RTKs), including insulin receptor, insulin‐like growth factor receptor as well as their downstream effectors, mitogen‐activated protein kinase and phosphatidylinositol‐3‐kinase pathways. Furthermore, knockdown of Reg IV impacted the ability of insulin and EGF to stimulate downstream tyrosine phosphorylation. Knockdown of Reg IV in cancer cell lines inhibited anchorage‐dependent and anchorage‐independent (both soft‐agar and spheroid assays) cell growth and induced cell cycle arrest. This was accompanied by upregulation of p21 and p27. Transiently silencing Reg IV in cancer cells induced apoptosis and downregulated Bcl‐2. Conversely, stimulation of HCT116 cells with recombinant Reg IV induced Bcl‐2. Hsp27, a molecule implicated in drug resistance, was similarly modulated by Reg IV. Consistent with our observations with Reg IV siRNA‐mediated knockdown, monoclonal antibodies directed against Reg IV inhibited PC3 and KM12 cell growth. Collectively, Reg IV plays an important role in cancer by modulation of key signaling molecules including Hsp27, Bcl‐2 and multiple RTKs.

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The Protein Kinase Complement of the Human Genome

Cited by 7,242 publications

References 35 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Hotspot activating PRKD1 somatic mutations in polymorphous low-grade adenocarcinomas of the salivary glands

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

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