See also Signal Transduction

Enzyme linked receptors, when activated, either function directly as enzymes or are directly associated with enzymes that they activate. They are formed by single pass transmembrane proteins that have their ligand binding site outside the cell and their catalytic or enzyme binding site inside. The great majority of enzyme linked receptors are protein kinases or are associated with protein kinases and ligand binding to them causes the phosphorylation of specific sets of proteins.

Receptor Tyrosine Kinases (see outline) are one class of enzyme linked receptors that phosphorylate specific tyrosines on signaling proteins. The cascade of events for RTKs generally takes longer than those for GPCRs (minutes rather than seconds). Tyrosine kinase receptors bind an extracellular ligand and a rearrangement of the transmembrane receptor chains is induced so that the two kinase domains autophosporylate and create docking sites for docking proteins. Phosphorylated tyrosines serve as docking sites for a whole range of intracellular signaling proteins that usually share highly conserved phosphotyrosine binding domains such as  SH2 domains. Many signaling proteins also contain other protein modules that allow them to interact with other proteins as part of the signaling process such as the SH3 domain.

A whole range of intracellular signaling proteins can bind to the phosphotyrosines on activated receptor tyrosine kinases or on special docking proteins to help relay the signal onward. Some docked proteins are enzymes, such as phosphlipase C-y (PLC-y) which functions in the same way  as phospholipase C-B in connection with G protein linked receptors by activating the inositol phosphlipid signaling pathway thereby increasing cytosolic Ca2+ levels. Some signaling proteins are composed almost entirely of SH2 and SH3 domains and function asadaptors to couple tyrosine phosphorylated proteins to other proteins that do not have their own SH2 domains. For example, adaptor proteins such as Grb-2 help couple activated receptors to the downstream signaling protein ras. The Grb-2 protein binds through its SH2 domain to specific phosphotyosines on activated receptor tyrosine kinases and through its SH3 domains to a GEF called Sos. The assembly of the complex receptor-Grb-2-Sos brings Sos into position to activate neighboring Ras by stimulating it to exchange its bound GDP for GTP. Ras activates multi downstream pathways including the MAP-kinase pathway which is important in gene expression and for regulating protein activity.

—Insulin-like growth factor receptor (IGF-1R) (see Receptor Tyrosine Kinases): is a ubiquitous transmembrane tyrosine kinase receptor that is essential for normal fetal and post-natal growth and development. IGF-1R can stimulate cell proliferation, cell differentiation, changes in cell size, and proteins cells form apoptosis. The IGF-1R is located on the cell surface of most cell types and serves as the signaling molecule for growth factors IGF-I and IGF-II (collectively termed IGFs). IGF-1R is highly similar to the insulin receptor (IR).

Signaling Pathways:

Phosphatidylinositol 3-kinase (PI 3-kinase) is an intracellular signaling pathway leading to cell growth. This kinase principally phosphorylates inositol phospholipids rather than proteins and it can be activated by receptor tyrosine kinases. When activated PI3-kinase catalyzes the phosphrylation of inositol phospholipids at the 3 position of the inositol ring to generate lipids called PI(3,4)P2 or PI(3,4,5)P3. Intracellular signaling proteins bind to the PI(3,4)P2 and PI(3,4,5)P3 mainly through their pleckstrin homology (PH) domain. For example, PI3-kinase signals cells to survive by indirectly activatingprotein kinase B (PKB) (also called Akt) which is a kinase with a PH domain.

It is important to distinguish the inositol phospholipids PI(3,4)P2 and PI(3,4,5)P3 from PI(4,5)P2 which is cleaved by PLCB (in the case of G protein linked receptors) or PLC-y (in the case of receptor tyrosin kinases) to generate soluble IP3 and membrane bound diacylglycerol. PI(3,4)P2 and PI(3,4,5)P3 are not cleaved by PLC.