hd-ptp is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domainhd-ptp是催化地不活跃的酪氨酸磷酸酶由于守恒的散度的磷酸酶域.pdfVIP

HD-PTP Is a Catalytically Inactive Tyrosine Phosphatase Due to a Conserved Divergence in Its Phosphatase Domain 1 1 1 2 2 Marie-Claude Gingras , Yu Ling Zhang , Dmitri Kharitidi , Alastair J. Barr , Stefan Knapp , Michel L. 1 1 Tremblay , Arnim Pause * ´ ´ 1 Goodman Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada, 2 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Abstract Background: The HD-PTP protein has been described as a tumor suppressor candidate and based on its amino acid sequence, categorized as a classical non-transmembrane protein tyrosine phosphatase (PTP). To date, no HD-PTP phosphorylated substrate has been identified and controversial results concerning its catalytic activity have been recently reported. Methodology and Results: Here we report a rigorous enzymatic analysis demonstrating that the HD-PTP protein does not harbor tyrosine phosphatase or lipid phosphatase activity using the highly sensitive DiFMUP substrate and a panel of different phosphatidylinositol phosphates. We found that HD-PTP tyrosine phosphatase inactivity is caused by an evolutionary conserved amino acid divergence of a key residue located in the HD-PTP phosphatase domain since its back mutation is sufficient to restore the HD-PTP tyrosine phosphatase activity. Moreover, in agreement with a tumor suppressor activity, HD-PTP expression leads to colony growth reduction in human cancer cell lines, independently of its catalytic