Are Parallel Proliferation Pathways Redundant?. Issue 7 (July 2020)

• Record Type: Journal Article
• Authors: Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum
• Is Part Of: Trends in biochemical sciences. Volume 45:Issue 7(2020)
• Page Start: 554
• Page End: 563
• Publication Date: 2020-07
• Subjects: drug resistance -- chromatin accessibility -- precision medicine initiative -- signaling -- K-Ras -- isoforms -- cancer -- free energy landscape; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2020.03.013
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Are the receptor tyrosine kinase (RTK) and JAK-STAT-driven proliferation pathways 'parallel' or 'redundant'? And what about those of K-Ras4B versus N-Ras? 'Parallel' proliferation pathways accomplish a similar drug resistance outcome. Thus, are they 'redundant'? In this paper, it is argued that there is a fundamental distinction between 'parallel' and 'redundant'. Cellular proliferation pathways are influenced by the genome sequence, 3D organization and chromatin accessibility, and determined by protein availability prior to cancer emergence. In the opinion presented, if they operate the same downstream protein families, they are redundant; if evolutionary-independent, they are parallel. Thus, RTK and JAK-STAT-driven proliferation pathways are parallel; those of Ras isoforms are redundant. Our Precision Medicine Call to map cancer proliferation pathways is vastly important since it can expedite effective therapeutics. Highlights: Proliferation pathways are determined by the genome sequence, 3D organization and chromatin accessibility, and influenced by protein availability prior to cancer emergence. Parallel proliferation pathways lead to the same function, albeit through different routes. Parallel proliferation pathways can lead to cell robustness as in the case of drug resistance; however, the emergence of cancer signaling pathways is context-dependent, associated with organ-specific cell lineage and the microenvironment. Proliferation pathways are cell type and state specific. If the pathways populating the same cell type involve the same proteins (nodes), or proteins of the same families they are 'redundant'; if different, they are 'parallel'; the smaller chromatin alteration suggests that redundant pathways are more pervasive.