Enzymes, proteins, riboproteins and signaling pathways.

receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are involved in signal transduction, and process a variety of environmental and intercellular cues. By contrast, protein tyrosine kinases (PTKs) are non-receptor, cytoplasmic enzymes that catalyze the phosphorylation of tyrosine residues.

Of the 91 protein tyrosine kinases identified, 59 are receptor tyrosine kinases and 32 are non-receptor, cellular tyrosine kinases. More than 70% of known oncogenes and proto-oncogenes (cancer) code for PTKs.

As central components of cell signaling networks, RTKs play crucial play crucial roles in physiological processes, such as embryogenesis, differentiation, neurite outgrowth, cell proliferation, anti-apoptotic signaling and death of cells (apoptosis). Some signaling molecules act as adhesion receptors, which cluster in focal adhesions upon ligand binding. Focal adhesions are rich in tyrosine phosphorylated proteins, coupling cell adhesion to signal transduction pathways in the cell. Various adhesion receptors, such as integrin, are closely linked to protein kinases and phosphatases.

RTKs comprise four domains:
1. extracellular ligand binding domain.
2. intracellular tyrosine kinase domain - amino acid sequences in ATP binding and substrate binding regions highly conserved with those of cAMP-dependent Protein Kinase (cAPK, PKA).
3. intracellular regulatory domain.
4. transmembrane domain.

RTKs are anchored in the plasma membrane at the transmembrane domain, while the extracellular domains bind growth factors. Typically, extracellular domains comprise structural motifs including acidic regions, cadherin-like domains, cysteine-rich regions, discoidin-like domains, EGF-like domains, Factor VIII-like domains, fibronectin III-like domains, glycine-rich regions, immunoglobulin-like domains, kringle-like domains, and leucine-rich regions.

Tables  Receptor Tyrosine Kinases(RTK)  Cell signaling :

The intracellular kinase domains of receptor PTKs (RTKs) are divided into two classes:
a) those containing a stretch of amino acids separating the kinase domain, and
b) those in which the kinase domain is continuous.

Activation of the kinase is effected by binding of a ligand to the extracellular domain, which induces dimerization of the receptors. Activated receptors autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation. This auto-phosphorylation stabilizes the active receptor conformation and creates phosphotyrosine docking sites for proteins that transduce signals within the cell.

Signaling proteins that bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include RasGAP, PI3-kinase, phospholipase C , phosphotyrosine phosphatase SHP and adaptor proteins such as Shc, Grb2 and Crk. Grb2 links focal adhesion kinase (FAK) to the Ras pathway when Grb2 is phosphorylated after binding to FAK. The 85 kDa subunit of the PI 3-kinase is also phosphorylated after binding to FAK. Thus, FAK is a key component in the assembly of focal contact structures that influence cytoskeletal organization and signal transduction.

In contrast to receptor-PTKs (RTKs), cellular PTKs are located in the cytoplasm, the nucleus, or are anchored to the inner leaflet of the plasma membrane. Cellular PTKs are grouped into eight families: SRC, JAK, ABL, FAK, FPS, CSK, SYK and BTK, each with several members. Except for homologous kinase domains (Src Homology 1, or SH1 domains), and some protein- protein interaction domains (SH2 and SH3 domains), the PTK families share little structurally. Of the cellular PTKs with known functions, many, such as SRC, are involved in cell growth. FPS PTKs are involved in differentiation, ABL PTKs participate in growth inhibition, and FAK activity is associated with cell adhesion. Some members of the cytokine receptor pathway interact with JAKs, which phosphorylate the transcription factors, STATs.

PTKs are hyperactivated in several human solid tumours and blood malignancies, and elevated levels contribute to tumourigenesis factors such as hyperplasia, survival, invasion, metastasis and angiogenesis. PTKs of the Src family (SFKs) are activated and overexpressed in approximately 80% of colon tumours; EGFR family PTKs are overexpressed/activated in the most breast and lung carcinomas and primary glioblastomas; and, EpH receptor PTKs are overexpressed in most melanomas.

Tables  Cell signaling  Receptor Tyrosine Kinases(RTK) :• phosphotransfer-mediated signaling pathwaysProtein Kinase Signaling Networksreceptor tyrosine kinases •  Receptor Tyrosine Kinases (RTKs)signaling gradientstwo-component systems • animation MAPK signal transduction : animation G-protein :

:Signaling pathways:Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) :: Evolution of Protein Kinase Signaling :

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