Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation
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Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation László Buday 1,2 & Virág Vas 1 Received: 7 June 2020 / Accepted: 19 June 2020 # The Author(s) 2020
Abstract Somatic mutations in the RAS genes are frequent in human tumors, especially in pancreatic, colorectal, and non-small-cell lung cancers. Such mutations generally decrease the ability of Ras to hydrolyze GTP, maintaining the protein in a constitutively active GTP-bound form that drives uncontrolled cell proliferation. Efforts to develop drugs that target Ras oncoproteins have been unsuccessful. Recent emerging data suggest that Ras regulation is more complex than the scientific community has believed for decades. In this review, we summarize advances in the “textbook” view of Ras activation. We also discuss a novel type of Ras regulation that involves direct phosphorylation and dephosphorylation of Ras tyrosine residues. The discovery that pharmacological inhibition of the tyrosine phosphoprotein phosphatase SHP2 maintains mutant Ras in an inactive state suggests that SHP2 could be a novel drug target for the treatment of Ras-driven human cancers. Keywords Ras . Ras signaling . SOS . Tyrosine phosphorylation . SHP2 . Cancer therapy
1 Introduction The products of the RAS family of proto-oncogenes are lowmolecular-weight guanine nucleotide-binding proteins that mediate cell growth, survival, and differentiation via interactions with a variety of effector proteins [1, 2]. Ras proteins are enzymes capable of hydrolyzing bound GTP to GDP and inorganic phosphate. Cycling between GDP-bound inactive and GTP-bound active forms is facilitated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAPs) via a mechanism that is common in the Ras superfamily [3, 4]. The three human RAS genes encode four highly similar proteins: H-Ras, N-Ras, and K-Ras4A and K-Ras4B. The expression of two protein products from the mammalian K-RAS gene results from the use of alternative fourth exons. Single-base substitutions in codons 12, 13, or 61 of RAS are among the most frequent oncogenic mutations in human cancers [5]. These mutations activate Ras by eliminating its GTP
* László Buday [email protected] 1
Institute of Enzymology, Research Centre for Natural Sciences, Budapest 1117, Hungary
2
Department of Medical Chemistry, Semmelweis University Medical School, Budapest 1094, Hungary
hydrolysis activity. Despite the high degree of similarity between the isoforms, K-Ras is the most frequently mutated; indeed, K-Ras mutations have been identified in 22% of all tumors investigated (compared with 8% for N-Ras and 3% for H-Ras) [6, 7].
1.1 Conventional regulation of Ras activation The first conceptualization of Ras activation was established in the early 1990s. According to this early model, growth factors, e.g., epidermal growth factor (EGF), induce a rapid dimerization and autophosphorylation of their receptors at the plasma membrane. Phosphotyrosine residues in the noncatalytic region of the receptors bind a variety of
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