PTPRT

2OOQ1112219281ENSG00000196090ENSMUSG00000053141O14522Q99M80NM_007050NM_133170NM_001291149NM_001291150NM_001291151NM_021464NP_008981NP_573400NP_001278078NP_001278079NP_001278080NP_067439Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene. Receptor-type tyrosine-protein phosphatase T is an enzyme that in humans is encoded by the PTPRT gene. PTPRT is also known as PTPrho, PTPρ and human accelerated region 9. The human accelerated regions are 49 regions of the human genome that are conserved among vertebrates, but in humans show significant distinction from other vertebrates. This region may, therefore, have played a key role in differentiating humans from apes. The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPrho has been proposed to function during development of the nervous system and as a tumor suppressor in cancer. This PTP possesses an extracellular region, a single transmembrane region, and two tandem intracellular catalytic domains, and thus represents a receptor-type PTP (RPTP). The extracellular region contains a meprin-A5 antigen-PTPmu (MAM) domain, one Ig-like domain and four fibronectin type III-like repeats. PTPrho is a member of the type R2B subfamily of RPTPs, which also includes the RPTPs PTPmu (PTPRM), PTPkappa (PTPRK), and PCP-2 (PTPRU). Comparison of R2B cDNA sequences identified that PTPmu is most closely related to PTPrho. PTPrho is alternatively spliced. Alternative splicing of exons 14, 16, and 22a have been described for PTPrho (PTPRT). Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. The first isoform encodes the larger version of the protein. The second variant lacks a region of the extracellular domain between the fourth FNIII domain and the transmembrane domain and in the juxtamembrane domain. PTPrho protein mediates homophilic cell-cell adhesion, meaning that when it interacts with a like molecule on an adjacent cell it induces the cells to bind or adhere to one another. PTPrho does not bind to other subfamily members to mediate cell-cell aggregation, similar to other type R2B subfamily members. The MAM domain, Ig domain and all four fibronectin III domain of PTPrho are necessary for cell-cell aggregation. PTPrho is the most frequently mutated RPTP in colon, lung, skin and stomach cancers. Many of the mutations observed in cancer occur in the extracellular domain of PTPrho, suggesting that defective cell-cell aggregation may contribute to the tumorigenicity of these mutations. When PTPrho proteins are engineered with the different point mutations observed in cancer and then are expressed in non-adherent Sf9 cells, these cells do not mediate comparable levels of cell-cell aggregation to wild-type PTPrho, demonstrating that the mutations observed in cancer are loss of function mutations. The first catalytic domain of Type R2B RPTPs is considered the active phosphatase domain, whereas the second phosphatase domain is thought to be inactive. Mutations in the second phosphatase domain of PTPrho, however, result in a reduction of phosphatase activity of PTPrho. Deletion of the second tyrosine phosphatase domain in colorectal cancer cells also reduces PTPrho catalytic activity, again demonstrating that the second phosphatase domain of PTPrho does regulate catalytic activity, either directly or indirectly. Catalytic activity of PTPrho may also be regulated by tyrosine phosphorylation of the wedge domain of the first tyrosine phosphatase domain on tyrosine 912 by Fyn tyrosine kinase. Tyrosine phosphorylation of Y912 results in increased multimerization of PTPrho, likely in cis, with other PTPrho molecules. Based on crystal structure analysis and modeling, the phosphorylated wedge domain is hypothesized to insert into the catalytic domain of a neighboring PTPrho molecule, thus inactivating it. This mechanism has also been proposed to regulate the catalytic activity of RPTPalpha. The crystal structures of PTPmu and LAR suggest a different mechanism for the regulation of their catalytic activity, as these RPTPs are in an open and active conformation when dimerized. Evaluation of the 5’untranslated regions of PTPrho (PTPRT) cDNA indicate a number of transcription factor binding site consensus sequences, including those for AP-2, c-Myb, NF-1, sox-5, and Sp-1, Oct-1, CdxA, C/EBP, En-1, GATA-1, GATA-2, GKLF, HoxA3, Ik-2, Msx-1, Pax-4 and SRY.