Second Messengers

One target for certain Ga(GTP) types is the enzyme adenyl cyclase. This enzyme uses ATP to generate cyclic AMP (cAMP). The cAMP molecule is a "second messenger," one of a family of small diffusible substances that powerfully induce cytoplasmic responses.

Cyclic AMP exerts much of its effects by activating the cAMP-dependent protein kinase (PKA), a ser/thr kinase that can phosphorylate and influence many cellular proteins. For example, PKA phosphorylates CREB (cyclic AMP response element binding protein), which is found attached to the promoters of many genes. Phosphorylation of CREB by PKA can thus regulate the expression of these genes.

Another Ga(GTP) target is an enzyme, phospholipase C, which cleaves a membrane lipid called PIP-2. This produces two products: DAG and IP-3. DAG stays in the membrane and binds all members of the ser/thr protein kinase C (PKC) family of enzymes, which may then become activated plasma membrane outer membrane of the cell

Activated RTK binds SH2 proteins, which can then act as their substrates (A) to form products (B).

growth factor growth factor tyrosine-, kinase U domain -I

inactive RTKs

endoplasmic reticulum network of membranes within the cell transcription factors proteins that increase the rate of gene transcription apoptosis programmed cell death and phosphorylate and regulate a host of metabolic and structural enzymes. IP-3, another second messenger, rapidly diffuses to IP-3 receptors in the endoplasmic reticulum membrane. When IP-3 binds, it opens channels in the membrane, releasing stored calcium into the cytoplasm. Calcium is normally kept at very low levels in the cytoplasm, and even small increases cause numerous major effects, so that calcium is also regarded as a powerful second messenger. These effects include the activation of various calcium binding proteins such as calmodulin and its many relatives. The calcium-bound versions of these proteins regulate many other enzymes. For example, calcium activates all members of a large and important family of ser/thr kinases called calcium/calmodulin dependent protein kinases (CAM kinases), which themselves regulate the activity of numerous important substrate molecules.

Just as protein kinases need to be turned off, so too do G proteins. This occurs when the GTP on the Ga is cleaved to generate GDP, thus favoring the reformation of the three-part inactive protein.

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