Functional and Structural Insights into RAS Effector Proteins

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 Jul 18

PMID 39025071

Authors

Alessandro M Mozzarelli

Dhirendra K Simanshu

Pau Castel

Affiliations

Soon will be listed here.

Abstract

RAS proteins are conserved guanosine triphosphate (GTP) hydrolases (GTPases) that act as molecular binary switches and play vital roles in numerous cellular processes. Upon GTP binding, RAS GTPases adopt an active conformation and interact with specific proteins termed RAS effectors that contain a conserved ubiquitin-like domain, thereby facilitating downstream signaling. Over 50 effector proteins have been identified in the human proteome, and many have been studied as potential mediators of RAS-dependent signaling pathways. Biochemical and structural analyses have provided mechanistic insights into these effectors, and studies using model organisms have complemented our understanding of their role in physiology and disease. Yet, many critical aspects regarding the dynamics and biological function of RAS-effector complexes remain to be elucidated. In this review, we discuss the mechanisms and functions of known RAS effector proteins, provide structural perspectives on RAS-effector interactions, evaluate their significance in RAS-mediated signaling, and explore their potential as therapeutic targets.

Citing Articles

Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance.

Ellis H, Braconi C, Valle J, Bardeesy N Am J Pathol. 2024; 195(3):437-452.

PMID: 39730074 PMC: 11841491. DOI: 10.1016/j.ajpath.2024.11.005.

Ras signaling mechanisms: New insights from single-molecule biophysics.

McCombs A, Armendariz J, Falke J Biophys J. 2024; 123(19):3277-3280.

PMID: 39217418 PMC: 11480753. DOI: 10.1016/j.bpj.2024.08.025.

References

Li Y, Chen C, Chang E . Fission yeast Ras1 effector Scd1 interacts with the spindle and affects its proper formation. Genetics. 2000; 156(3):995-1004. PMC: 1461343. DOI: 10.1093/genetics/156.3.995. View

Castel P, Dharmaiah S, Sale M, Messing S, Rizzuto G, Cuevas-Navarro A . RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity. Proc Natl Acad Sci U S A. 2021; 118(33). PMC: 8379911. DOI: 10.1073/pnas.2103261118. View

Ferguson E, Sternberg P, Horvitz H . A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans. Nature. 1987; 326(6110):259-67. DOI: 10.1038/326259a0. View

Murthy M, Schwarz T . The exocyst component Sec5 is required for membrane traffic and polarity in the Drosophila ovary. Development. 2003; 131(2):377-88. DOI: 10.1242/dev.00931. View

Sternberg P, Han M . Genetics of RAS signaling in C. elegans. Trends Genet. 1998; 14(11):466-72. DOI: 10.1016/s0168-9525(98)01592-3. View

Martinez Fiesco J, Durrant D, Morrison D, Zhang P . Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding. Nat Commun. 2022; 13(1):486. PMC: 8789793. DOI: 10.1038/s41467-022-28084-3. View

Isomura M, Okui K, Fujiwara T, Shin S, Nakamura Y . Isolation and mapping of RAB2L, a human cDNA that encodes a protein homologous to RalGDS. Cytogenet Cell Genet. 1996; 74(4):263-5. DOI: 10.1159/000134431. View

Randelovic I, Nyiri K, Koppany G, Baranyi M, Tovari J, Kigyos A . Gluing GAP to RAS Mutants: A New Approach to an Old Problem in Cancer Drug Development. Int J Mol Sci. 2024; 25(5). PMC: 10932042. DOI: 10.3390/ijms25052572. View

Li Y, Chang E . Schizosaccharomyces pombe Ras1 effector, Scd1, interacts with Klp5 and Klp6 kinesins to mediate cytokinesis. Genetics. 2003; 165(2):477-88. PMC: 1462777. DOI: 10.1093/genetics/165.2.477. View

10.

Wheatley E, Rittinger K . Interactions between Cdc42 and the scaffold protein Scd2: requirement of SH3 domains for GTPase binding. Biochem J. 2005; 388(Pt 1):177-84. PMC: 1186706. DOI: 10.1042/BJ20041838. View

11.

Ferguson E, Horvitz H . Identification and characterization of 22 genes that affect the vulval cell lineages of the nematode Caenorhabditis elegans. Genetics. 1985; 110(1):17-72. PMC: 1202554. DOI: 10.1093/genetics/110.1.17. View

12.

Amendola C, Mahaffey J, Parker S, Ahearn I, Chen W, Zhou M . KRAS4A directly regulates hexokinase 1. Nature. 2019; 576(7787):482-486. PMC: 6923592. DOI: 10.1038/s41586-019-1832-9. View

13.

Yen I, Shanahan F, Merchant M, Orr C, Hunsaker T, Durk M . Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors. Cancer Cell. 2018; 34(4):611-625.e7. DOI: 10.1016/j.ccell.2018.09.002. View

14.

Van Aelst L, Barr M, MARCUS S, Polverino A, Wigler M . Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci U S A. 1993; 90(13):6213-7. PMC: 46898. DOI: 10.1073/pnas.90.13.6213. View

15.

Emerson S, Madison V, Palermo R, Waugh D, Scheffler J, Tsao K . Solution structure of the Ras-binding domain of c-Raf-1 and identification of its Ras interaction surface. Biochemistry. 1995; 34(21):6911-8. DOI: 10.1021/bi00021a001. View

16.

Okada T, Hu C, Jin T, Kariya K, Kataoka T . The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family small GTPases. Mol Cell Biol. 1999; 19(9):6057-64. PMC: 84512. DOI: 10.1128/MCB.19.9.6057. View

17.

Coyle S, Lim W . Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution. Elife. 2016; 5. PMC: 4775219. DOI: 10.7554/eLife.12435. View

18.

. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015; 517(7536):576-82. PMC: 4311405. DOI: 10.1038/nature14129. View

19.

Liau N, Wendorff T, Quinn J, Steffek M, Phung W, Liu P . Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization. Nat Struct Mol Biol. 2020; 27(2):134-141. DOI: 10.1038/s41594-019-0365-0. View

20.

Wu Y, Han M . Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Genes Dev. 1994; 8(2):147-59. DOI: 10.1101/gad.8.2.147. View