Functional transition of Pak proto-oncogene during early evolution of metazoans

Abstract

Proto-oncogenes encode signaling molecular switches regulating cellular homeostasis in metazoans, and can be converted to oncogenes by gain-of-function mutations. To address the molecular basis for development of the regulatory system of proto-oncogenes during evolution, we screened for ancestral proto-oncogenes from the unicellular choanoflagellate Monosiga ovata by monitoring their transforming activities, and isolated a Pak gene ortholog encoding a serine/threonine kinase as a 'primitive oncogene'. We also cloned Pak orthologs from fungi and the multicellular sponge Ephydatia fluviatilis, and compared their regulatory features with that of M. ovata Pak (MoPak). MoPak is constitutively active and induces cell transformation in mammalian fibroblasts, although the Pak orthologs from multicellular animals are strictly regulated. Analyses of Pak mutants revealed that structural alteration of the auto-inhibitory domain (AID) of MoPak confers higher constitutive kinase activity, as well as greater binding ability to Rho family GTPases than the multicellular Paks, and this structural alteration is responsible for cell transformation and disruption of multicellular tissue organization. These results show that maturation of AID function was required for the development of the strict regulatory system of the Pak proto-oncogene, and suggest a potential link between the establishment of the regulatory system of proto-oncogenes and metazoan evolution.

Constitutive Activity in an Ancestral Form of Abl Tyrosine Kinase

“…Our data are consistent with a model in which the regulatory elements for Abl kinases evolved later in the metazoan lineage. We and others have postulated similar processes for the Src and Pak proto-oncogenes [ 17 , 38 , 46 ]. A caveat is that the M .…”

Nonsynonymous, synonymous and nonsense mutations in human cancer-related genes undergo stronger purifying selections than expectation

“…Natural selection exists among all living organisms [1]. Mutation is the major source of selection and adaptation [2–5]. In coding region of DNA, it is imaginable that the nonsynonymous mutations that change the protein sequences would undergo strong selection, and those nonsense mutations that cause pre-mature termination of protein synthesis are also highly deleterious and subjective to purifying selection.…”

“…For cancer researches, analyzing the patient data is undoubtedly the most efficient and direct approach, but the accessibility of some newly emerged cancer data is a problem to the vast majority of scientific researchers. Thus, digging out some valuable information in cancer-related genes from the commonly available human genome data (or even data in other species) is suitable for most researchers or evolutionary biologists [2].…”

Src signaling in a low-complexity unicellular kinome

“…Other unicellular kinases display weak negative regulation, including M . ovata Src 30 and Pak 45 , M . brevicollis Src 26 and Abl 46 , and the Src-family kinases from the filastereans C .…”