Dimerization receptor tyrosine kinases

The insulin receptor is a dimeric receptor tyrosine kinase that can initiate the Ras-MAP kinase pathway, leading to changes in gene expression. Insulin stimulation also can initiate the PT3 kinase pathway just described, leading to activation of protein kinase B. In insulin-stimulated liver, muscle, and fat cells, activated protein kinase B acts in several ways to lower blood glucose and promote glycogen synthesis. 

FIGURE 4.2 Receptor tyrosine kinase dimerization. Binding of monomeric or dimeric ligands to RTK monomers leads to formation and stabilization of activated RTK dimers. Cytoplasmic domains of RTK are trans-phosphorylated by active FTK. 

Lenferink, A. E., R. Pinkas Kramarski, M. L. van de Poll, M. J. van Vugt, L. N. Klapper, E. Tzahar, H. Waterman, M. Sela, E. J. van Zoelen, and Y. Yarden. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J. 17 3385-3397.1998. 

Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric state (/eft) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently. The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y) and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins (S). 

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. 

Rodrigues GR, Park M. 1993. Dimerization through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol 13 6711-6722. 

The second example of cell-signaling process that involves protein phosphorylation is receptor tyrosine kinase signaling (Fig. 10) (42). Receptor tyrosine kinases are transmembrane proteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Ligand binding to the extracellular domain triggers receptor dimerization and/or activation, so that the intracellular catalytic domains from two receptor protein molecules can phosphorylate each other at the... 

Intrinsic tyrosine kinases are covalently incorporated in the intracellular domains of some receptors, such as epidermal growdh factor receptor and the insulin receptor. When such receptor tyrosine kinases dimerize, cross-phosphorylation occurs. The phosphorylated tyrosines in activated receptor tyrosine kinases serve as docking sites for SH2 domains present in numerous signaling proteins and permit further propagation of the signal. A prominent component of such pathways is the small GTPase Ras. The Ras protein, like the G subunit, cycles between an inactive form bound to GDP... 

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