Receptors tyrosine kinase, coupling

Receptor Tyrosine Kinase-coupled Second Messengers... 

Besides the cytokine receptors that lack intrinsic kinase activity but have associated JAK kinases, STAT proteins can be activated by a variety of G-protein coupled receptors and growth factor receptors with intrinsic tyrosine kinase activity (for example EGF, PDGF, CSF-1, and angiotensin receptor). Increasing evidence suggests a critical role for STAT family members in oncogenesis and aberrant cell proliferation. Constitutively activated STATs have been found in many transformed cell lines and a wide variety of human tumor entities. Numerous non-receptor tyrosine kinases and viral oncoproteins, such as v-Src, v-Abl, v-Sis, and v-Eyk, have been identified to induce DNA-binding activity of STAT proteins. 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

We discuss later a number of receptor classes and analyze how signals are transduced. These receptors are G-protein coupled receptors (GPCRs), ion channel receptors, tyrosine kinases, and intracellular receptors. A list of selected... 

The functions of transmembrane receptors can be modified using adaptor motecules. Sometimes the adaptors bring in substrates to the receptor s enzyme activity, but other times they can bring in the activity itsetf. The best known adaptors have protein structurai domains called SH2 or SH3 domains. These adaptors couple various functions to receptor tyrosine kinases (Fig. 9-4). SH2 and SH3 stands for Src homotogy region 2 and 3 because they were discovered first in the oncogene, Src (see tater). These adapters recognize specific phosphotyrosine residues in the autophosphorylated receptor. Src itsetf is not a receptor, but it is a tyrosine kinase. It has an SH2 and SH3 domain to tink it to the receptor and, when this occurs, it becomes activated as a tyrosine kinase. 

Signaling pathways starting from receptor tyrosine kinases trigger stimulation of protein kinase C by activating phosphohpase Cy. An activating signal may also be despatched in the direction of protein kinase C - via activation of phospholipase CP -from G-protein-coupled membrane receptors (see Fig. 6.4). 

Some transmembrane receptors possess intrinsic tyrosine kinase activity. These receptors are known as receptor tyrosine kinases. Ligand binding to an extracellular domain of the receptor is coupled to the stimulation of tyrosine kinase activity localized on a cytoplasmic receptor domain. The ligand binding domain and the tyrosine kinase domain are part of one and the same protein. 

Intracellular signal transduction employs central switching stations that receive, modulate and transmit signals further. The Ras proteins (also known as p2T proteins) make up a switching station of particular importance for growth and differentiation processes. The Ras proteins process signals received by receptor tyrosine kinases, by receptors with associated tyrosine kinase activity and by G-protein-coupled receptors, and transmit these into the cell interior (Fig. 9.1). 

Fig. 9.1. The Ras protein as a central switching station of signaling pathways. A main pathway for Ras activation is via receptor tyrosine kinases, which pass the signal on via adaptor proteins and guanine nucleotide exchange factors to the Ras protein. Activation ofRas protein can also be initiated via G-protein-coupled receptors and via transmembrane receptors with associated tyrosine kinase activity. The membrane association of the Ras protein (see Fig. 9.6) is not shown for clarity. In addition, not aU signahng pathways that contribute to activation of the Ras protein are shown, nor are all effector reactions. Py omplex of the heterotrimeric G proteins GAP GTPase activating protein GEF guanine nucleotide exchange factor.

Fig. 9.12. Overview of the Ras signaling pathway. Signals from at least three major signaling pathways meet at the Ras protein. Activation of the Ras protein may be initiated by receptor tyrosine kinases, by G-protein-coupled receptors and by receptors with associated tyrosine kinases. The nature of the communication between the Ras protein and receptors with associated tyrosine kinase or G-protein-coupled receptors is mostly unknown. From the activated Ras protein, the signal is passed to various effector molecules including members of the MEK kinases, PI3-kinase, pl20 GAP and Ral-GEFs. The best understood is the effector function of Raf kinase, which passes a signal to the transcription level via the MAP kinase pathway.

Abbreviations-. GPCR = G protein coupled receptor RXR = retinoid X receptor RTK = receptor tyrosine kinase RSTK = receptor serine/threonine kinase RACK = receptor for activated protein kinase C MAPK = mitogen-activated protein kinase. 

Transmembrane receptors include G-protein-coupled receptors, receptor tyrosine kinases, integrins, pattern-recognition receptors and hgand-activated ion channels. 

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