Irandoust Mahban, van den Berg Timo K, Kaspers Gertjan J L, Cloos Jacqueline
Department of Pediatric Oncology/Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands.
Anticancer Agents Med Chem. 2009 Feb;9(2):212-20. doi: 10.2174/187152009787313864.
Protein tyrosine phosphorylation is one of the key mechanisms involved in signal transduction pathways. This modification is regulated by concerted action of protein tyrosine phosphatases and protein tyrosine kinases. Deregulation of either of these key regulators lead to abnormal cellular signaling, which is largely associated with human pathologies including cancer. Although the role of protein tyrosine kinases in cancer is well established, less is known about the involvement of protein tyrosine phosphatases in carcinogenesis and tumor progression. Moreover, several inhibitors targeting protein tyrosine kinases have demonstrated their value in cancer treatment, while interest in protein tyrosine phosphatases as a target for treatment has risen more recently. In this review we describe the progressive efforts and challenges concerning the development of drugs targeting phosphatases as promising novel cancer therapies. We focus on two key regulatory SH2 domain-containing phosphatases, SHP-1 and SHP-2 and one of their substrates, signal regulatory protein alpha. Since SHPs have been linked to many different malignancies, protein tyrosine phosphatases could offer a great spectrum of new, targeted drugs.
蛋白质酪氨酸磷酸化是信号转导通路中的关键机制之一。这种修饰由蛋白质酪氨酸磷酸酶和蛋白质酪氨酸激酶的协同作用调控。这些关键调节因子中任何一个的失调都会导致异常的细胞信号传导，这在很大程度上与包括癌症在内的人类疾病相关。尽管蛋白质酪氨酸激酶在癌症中的作用已得到充分证实，但关于蛋白质酪氨酸磷酸酶在致癌作用和肿瘤进展中的参与情况却知之甚少。此外，几种靶向蛋白质酪氨酸激酶的抑制剂已在癌症治疗中显示出其价值，而最近将蛋白质酪氨酸磷酸酶作为治疗靶点的兴趣也有所增加。在这篇综述中，我们描述了在开发靶向磷酸酶的药物作为有前景的新型癌症疗法方面的渐进努力和挑战。我们重点关注两种关键的含SH2结构域的调节性磷酸酶，即SHP-1和SHP-2以及它们的一种底物，信号调节蛋白α。由于SHP与许多不同的恶性肿瘤有关，蛋白质酪氨酸磷酸酶可能会提供大量新的靶向药物。
