Abstract LB-058: Novel interactions of the RAS oncoprotein
Authors: Shankar Sunita , Malik Rohit , Kothari Vishal , Hosono Yasuyuki , Pitchiaya Sethuramasundaram , Kalyana-Sundaram Shanker , Yocum Anastasia , Escara-Wilke June , Gundlapalli Harika , Chinnaswamy Krishnapriya , Shuler Matthew , Poliakov Anton , Wang Xiaoju , Krishnan Vishalakshi , White Yasmine , Firestone Ari , Cao Xuhong , Dhanasekaran Saravana M. , Stuckey Jeanne , Bollag Gideon , Shannon Kevin , Walter Nils G. , Kumar-Sinha Chandan , Chinnaiyan Arul 
Published: August 2015

Approximately 30% of all cancers harbor activating mutations in the RAS family of small GTPase proteins, making it one of the most common oncogenic aberrations in humans. Normal RAS proteins (H, K or N-RAS) localize to the inner cell membrane and transduce extracellular growth signals by cycling between an “active” GTP-bound state and “inactive” GDP-bound state, through interactions with various “GTPase activating proteins” (GAPs) that promote RAS mediated GTP hydrolysis. Oncogenic mutants of RAS lose their catalytic activity or association with the GAP proteins, resulting in constitutively active GTP-bound state that signals through direct interactions with effector kinases like RAF and PI3K and activate the MEK/ERK and/or Akt, leading to activation of hallmark cancer pathways including growth factor independence, uncontrolled cell proliferation, evasion of apoptosis and immune responses, increased metabolism as well as metastases. Although RAS is the most frequently mutated gene driving multifarious pathways of oncogenesis, our knowledge of protein interactions involving RAS proteins have been largely limited to RAS binding domains in RAF/PI3K/RalGDS. Targeting mutant RAS proteins or its direct effectors, or pathways activated by RAS effectors remains a challenging endeavor for treating RAS driven cancers.

Towards the goal of a thorough understanding of RAS biology through a comprehensive identification of its interactors, we performed IP-Mass Spectrometric analysis of pan-RAS immunoprecipitates from multiple cell lines. Interestingly in our experiments, apart from the well-known interactor RAF, we found evidence of several novel RAS interacting proteins, including many with DNA and RNA binding motifs. Our study validates these findings through cell-free protein interaction analyses and explores the possible biological effects of these novel RAS interactions in mutant KRAS driven cellular transformation.

Note: This abstract was not presented at the meeting.

Citation Format: Sunita Shankar, Rohit Malik, Vishal Kothari, Yasuyuki Hosono, Sethuramasundaram Pitchiaya, Shanker Kalyana-Sundaram, Anastasia Yocum, June Escara-Wilke, Harika Gundlapalli, Krishnapriya Chinnaswamy, Matthew Shuler, Anton Poliakov, Xiaoju Wang, Vishalakshi Krishnan, Yasmine White, Ari Firestone, Xuhong Cao, Saravana M. Dhanasekaran, Jeanne Stuckey, Gideon Bollag, Kevin Shannon, Nils G. Walter, Chandan Kumar-Sinha, Arul Chinnaiyan. Novel interactions of the RAS oncoprotein. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-058. doi:10.1158/1538-7445.AM2015-LB-058