Molecular BIology of Cancer Topics   

Signal Transduction Review

Protein Phosphorylation

Protein phosphorylation is a common mechanism in signal transduction. It is a is a reversibe post-translational modification that occurs rapidly (seconds, minutes vs. protein synthesis & degradation which takes hours or days). Protein phosphorylation can affect several properties of the protein: conformation, enzymatic activity and binding ability.

Two types of enzymes control the phosphorylation status of proteins: kinases and phosphatases. Kinases are enzymes that transfer a phosphate group from ATP to another molecule (e.g. another protein), while phosphatases are enzymes that remove a phosphate group.

Kinases can be classified as either serine/threonine kinases, tyrosine kinases or dual specificity kinases according to the amino acid residue that they phosphorylate. The majority of cellular protein kinases are Ser/Thr.

Similarly to kinases, phosphatases can be classified as Ser/Thr phosphatases, Tyr phosphatases or dual specificity phosphatases

Mitogenic Signaling

Many proteins relay mitogenic, i.e. growth stimulatory, signals (see Table 1). Nearly all of the signal-transducing proteins are encoded by proto-oncogenes. Conversely, nearly all known proto-oncogenes encode signal transducing proteins. Human cancers often exhibit autocrine growth signaling, with both the growth factor and its receptor being overexpressed. Overexpression of growth factors or their receptors can be detected by Western blot analysis of cancer vs. normal tissues, using antibodies especific to either the growth factor or its receptor.

The general structure of a growth factor receptor includes an extracellular ligand binding domain, single transmembrane domain, and cytoplasmic (intracellular) domain. The cytoplasmic domain has tyrosine kinase activity plus a Tyr residues within or near the tyrosine kinase domain. Upon binding the growth factor, the receptor dimerizes with another ligand-bound receptor, resulting in cross-phosphorylation of the tyrosine residue. In other words, the tyrosine kinase domain of one receptor phosphorylates the Tyr residue on the other receptor.

Several proteins can bind the receptors' phosphotyrosine residues via SH2 or SH3 domains. SH2 (Src homology 2) domains bind phosphotyrosine and the 3 amino acids that follow (P-YXXX). Proteins with SH2 domains include signal transmitters like Phospholipase C and Phosphoinositol 3’ phosphate kinase (PI3 kinase), and adapter proteins (that bridge to other signal transmitters) like GRB2 and Shc. SH3 (Src homology 3) domains bind proline-rich regions of other proteins. Each SH2 domain differs slightly in sequence and recognizes a different amino acid sequence following phosphotyrosine. A protein such as the PDGF receptor with multiple phosphotyrosine residues can bind more than one SH2-containing protein at a time, thus it is capable of activating multiple signaling cascades. After binding the receptor's phosphotyrosine residues, the signal transmitters are activated through Tyr phosphorylation by the receptor tyrosine kinase.

Many mitogenic signaling proteins are in the signaling pathway downstream of tyrosine kinase receptors. The Ras GTP-binding protein is an important protein that transduces signals from SH2 homology porteins activated by tyrosine kinases, for example Grb-2, to a kinase cascade that changes the phosphorylation status of transcription factors and other important proteins.

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