Functional analysis of a tumor suppressor candidate gene, HD-PTP, located on human chromosome 3p21

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A human HD-PTP cDNA encoding a novel protein tyrosine phosphatase has been isolated in our laboratory. The phosphatase has unique features in its domain structure : a Histidine-domain containing several SH3-binding motifs, a tyrosine phosphatase domain, a C-terminal PEST motif, and an N-terminal domain similar to yeast BRO1, an apoptpsis-related mammalian AIP1 and to a RHO-binding protein, Rhophilin. The gene is located at chromosome 3p21.3, an area frequently deleted in many types of cancer, especially within the functionally defined narrow region. The gene may be a human homolog of the rat PTP-TD14 gene reported by others, which can suppress H-ras- mediated transformation. The phosphatase gene may be a candidate for one of the tumor suppressor genes located on 3p21.3.To analyze the function of HD-PTP through the signal transduction, we screened new proteins, which can bind with each domain of HD-PTP, by yeast two-hybrid assay. As targets of BRO-domain, rabaptin 5, which is an effector of rab 5(GTPase protein), and HC8, which is proteosome alpha subunit and regulates the life time of cell cycle-related proteins, were isolated. It has been reported that tumor suppressor gene TSC2 product (tuberin) binds to rabaptin 5, suggesting that HD-PTP may be associated in the tumorigenesis through rabaptin 5/rab5 complex. As targets of Histidine-domain, DNA repair gene SOH1 was isolated. SOH1 is known to bind with the other repair enzymes and transcriptional factors, suggesting that HD-PTP may be associated with DNA repair system through transcription.