Regulating receptor PTP activity

Abstract

The structure of receptor protein tyrosine phosphatases (RPTPs) is indicative of function at the interface between extracellular environment and intracellular signaling cascades. RPTPs are extremely variable on their extracellular side, and display diverse protein motifs like immunoglobulin-like domains, fibronectin type III-like domains, RGDS adhesion recognition motifs, and heavily glycosylated domains. Intracellularly, RPTPs fall into two classes, those with one phosphatase domain, and others with two tandem phosphatase domains. Crystallographic studies and unique biochemical properties of RPTPs have begun elucidating novel intracellular mechanisms of regulation. Consequently, a number of models have been proposed that are being actively investigated. Recent data implicate an array of diverse mechanisms that regulate RPTP activity, some quite unconventional and unique to phosphatase biology. This chapter discusses some of the major regulatory models and recent advances in probing the fidelity of these mechanisms. Commensurate with their critical role in development and physiology, RPTP activity is very tightly controlled. The unique biology of phosphatases has led to the evolution of a number of intriguing mechanisms, including, but not limited to, dimerization, phosphorylation status, inactivation by reversible oxidation, and proteolytic processing. Apart from these mechanisms, there are other potential mechanisms, including those of alternative splicing, that may generate differentially localized isoforms that engage different subsets of interactors.