Dna

transcriptional activation

carboxyl-terminal domain marking protein for attachment of ubiquitin

- SH2 —^SH^^- SH2 -^P^- C2 b GTPase-activating — RasGAP

Transcription

Signal regulation

Phospholipid second-messenger signaling

Phospholipid second-messenger signaling

FIGURE 12-24 Some binding modules of signaling proteins. Each protein is represented by a line (with the amino terminus to the left); symbols indicate the location of conserved binding domains (with specificities as listed in the key; PH denotes plextrin homology; other abbreviations explained in the text); green boxes indicate catalytic ac

FIGURE 12-24 Some binding modules of signaling proteins. Each protein is represented by a line (with the amino terminus to the left); symbols indicate the location of conserved binding domains (with specificities as listed in the key; PH denotes plextrin homology; other abbreviations explained in the text); green boxes indicate catalytic ac tivities. The name of each protein is given at its carboxyl-terminal end. These signaling proteins interact with phosphorylated proteins or phospholipids in many permutations and combinations to form integrated signaling complexes.

Most of the proteins involved in signaling at the plasma membrane have one or more protein- or phos-pholipid-binding domains; many have three or more, and thus are multivalent in their interactions with other signaling proteins. Figure 12-24 shows a few of the many multivalent proteins known to participate in signaling.

A remarkable picture of signaling pathways has emerged from studies of many signaling proteins and the multiple binding domains they contain (Fig. 12-25). An initial signal results in phosphorylation of the receptor or a target protein, triggering the assembly of large multiprotein complexes, held together on scaffolds made from adaptor proteins with multivalent binding capacities. Some of these complexes have several protein kinases that activate each other in turn, producing a cascade of phosphorylation and a great amplification of the initial signal. Animal cells also have phosphotyrosine phosphatases (PTPases), which remove the phosphate from ®-Tyr residues, reversing the effect of phosphor-ylation. Some of these phosphatases are receptorlike membrane proteins, presumably controlled by extracellular factors not yet identified; other PTPases are soluble and contain SH2 domains. In addition, animal cells have protein phosphoserine and phosphothreonine phosphatases, which reverse the effects of Ser- and Thr-specific protein kinases. We can see, then, that signaling occurs in protein circuits, effectively hard-wired from signal receptor to response effector and able to be switched off instantly by the hydrolysis of a single phosphate ester bond.

The multivalency of signaling proteins allows for the assembly of many different combinations of signaling modules, each combination presumably suited to particular signals, cell types, and metabolic circumstances. The large variety of protein kinases and of phosphoprotein-binding domains, each with its own specificity (the consensus sequence required in its substrate), provides for many permutations and combinations and many different signaling circuits of extraordinary complexity. And given the variety of specific phosphatases that reverse

Insulin

Insulin

FIGURE 12-25 Insulin-induced formation of supramolecular signaling complexes. The binding of insulin to its receptor sets off a series of events that lead eventually to the formation of membrane-associated complexes involving the 12 signaling proteins shown here, as well as others. Phosphorylation of Tyr residues in the insulin receptor initiates complex formation, and dephosphorylation of any of the phospho-proteins breaks the circuit. Four general types of interaction hold the complex together: the binding of a protein to a second phosphopro-tein through SH2 or PTB domains in the first (red); the binding of SH3 domains in the first with proline-rich domains in the second (orange); the binding of PH domains in one protein to the phospholipid PIP3 in the plasma membrane (blue); or the association of a protein (RAS) with the plasma membrane through a lipid covalently bound to the protein (yellow). Two proteins shown here are not described in the text: 14-3-3, which binds a @-Ser in Raf and mediates its interaction with MEK; and MP1, a scaffold protein that cements the links between Raf, MEK, and ERK.

the action of protein kinases, some under specific types of external control, a cell can quickly "disconnect" the entire protein circuitry of a signaling pathway. Together, these mechanisms confer a huge capacity for cellular regulation in response to signals of many types.

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