A large body of evidence has linked tyrosine phosphorylation to the regulation of basic biological processes such as cell cycle processing, cellular differentiation, embryogenesis and transformation. The levels of intracellular tyrosine phosphorylation are regulated by the action of two gene families, protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP). Although over 103 PTPs have been isolated, it is still only recently that important functions have been directly associated with specific tyrosine phosphatases. The members of this family are extremely diverse and have been identified in prokaryotes to eukaryotes.
 The catalytic domain of the PTPs is highly conserved and is composed of approximately 220 amino acids sequence. Within this domain, the V/IHCSAGXGRXG sequence is well-conserved and it contains a Cys residue that is critical for the PTP activity. The mutation of this Cys residue to Ser abolishes the catalytic activity. However, these mutant PTPs also known as “substrate trapping mutants”, can still bind to their phosphorylated substrates and could further be used to identify the specific in vivo substrates. Supported by the recent generation of several PTP knock-out mouse models, we and others established that members of this gene family play key functions in many diseases and, in particular, in cancer. In the context of this presentation, we will review the role of one of the most important member of this family; PTP1b. We will review its crucial implication in diabetes and obesity and discuss our recent findings in breast and other cancers. Finally, we will close by describing existing and recent efforts to develop inhibitors of PTP1b in the treatments of these diseases.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA