REGULATION OF GROWTH FACTOR-INDUCED SIGNALING BY PROTEIN-TYROSINE-PHOSPHATASES

The binding of a growth factor to its specific receptor catalyzes a co mplex cascade of intracellular signaling events, characterized by chan ges in the phosphorylation state of many key proteins, Among these pho sphorylation events, tyrosine phosphorylation plays a prominent role i n the transmission of postreceptor signals, The state of tyrosine phos phorylation is regulated by the actions of protein-tyrosine kinases (P TKs) and protein-tyrosine-phosphatases (PTPs), Dysregulation of either event can lead to abnormal cellular responses, PTPs generally act to regulate negatively-that is, to turn off-any signals generated by PTKs , However, this is not always the case, as seen by the phosphatase SHP -2, which can either be a positive or negative regulator of signal tra nsduction depending on the particular cellular context, In addition, a novel family of dual specificity phosphatases has been recently disco vered. These enzymes are capable of dephosphorylating phosphotyrosine and phosphothreonine/phosphoserine residues, and seem to play a signif icant role in attenuating the action of MAP kinases, Several themes ap pear throughout PTP regulation of growth factor signaling, including p ositive or negative regulation, importance of cell/tissue type, identi ty of the receptor activated, and subcellular localization. Although o nly a handful of PTPs have been identified, the present work done in e lucidating their function has revealed their significance in the maint enance of normal physiological responses to growth factors.