Identification of a carbonic anhydrase-like domain in the extracellular region of RPTPγ defines a new subfamily of receptor tyrosine phosphatases

The tyrosine phosphatase RPTPγ is a candidate tumor suppressor gene since it is located on human chromosome 3_p14.2-_p21 in a region frequently deleted in certain types of renal and lung carcinomas. In order to evaluate its oncogenic potential and to explore its normal in vivo functions, we have isolated cDNAs and deduced the complete sequences of both human and murine RPTPγ. The murine RPTPγ gene has been localized to chromosome 14 to a region syntenic to the location of the human gene. Northern (RNA) blot analysis reveals the presence of two major transcripts of 5.5 and 8.5 kb in a variety of murine tissues. In situ hybridization analysis reveals that RPTPγ mRNA is expressed in specific regions of the brain and that the localization of RPTPγ changes during brain development. RPTPγ is composed of a putative extracellular domain, a single transmembrane domain, and a cytoplasmic portion with two tandem catalytic tyrosine phosphatase domains. The extracellular domain contains a stretch of 266 amino acids with striking homology to the zinc-containing enzyme carbonic anhydrase (CAH), indicating that RPTPγ and RPTPβ (HPTPζ) represent a subfamily of receptor tyrosine phosphatases. We have constructed a model for the CAH-like domain of RPTPγ based upon the crystal structure of CAH. It appears that 11 of the 19 residues that form the active site of CAH are conserved in RPTPγ. Yet only one of the three His residues that ligate the zinc atom and are required for catalytic activity is conserved. On the basis of this model we propose that the CAH-like domain of RPTPγ may have a function other than catalysis of hydration of metabolic CO₂.