蛋白质酪氨酸磷酸酶
癌变
MAPK/ERK通路
信号转导
变构调节
磷酸化
生物
PTPN11型
细胞生物学
SH2域
细胞信号
癌症
癌症研究
计算生物学
基因
遗传学
受体
突变
克拉斯
作者
Colin L. Welsh,Sarah Allen,Lalima K. Madan
出处
期刊:Advances in Cancer Research
日期:2023-01-01
卷期号:: 17-60
标识
DOI:10.1016/bs.acr.2023.03.003
摘要
Since the discovery of tyrosine phosphorylation being a critical modulator of cancer signaling, proteins regulating phosphotyrosine levels in cells have fast become targets of therapeutic intervention. The nonreceptor protein tyrosine phosphatase (PTP) coded by the PTPN11 gene "SHP2" integrates phosphotyrosine signaling from growth factor receptors into the RAS/RAF/ERK pathway and is centrally positioned in processes regulating cell development and oncogenic transformation. Dysregulation of SHP2 expression or activity is linked to tumorigenesis and developmental defects. Even as a compelling anti-cancer target, SHP2 was considered "undruggable" for a long time owing to its conserved catalytic PTP domain that evaded drug development. Recently, SHP2 has risen from the "undruggable curse" with the discovery of small molecules that manipulate its intrinsic allostery for effective inhibition. SHP2's unique domain arrangement and conformation(s) allow for a truly novel paradigm of inhibitor development relying on skillful targeting of noncatalytic sites on proteins. In this review we summarize the biological functions, signaling properties, structural attributes, allostery and inhibitors of SHP2.
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