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Ni Z, Cheng X. Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis. Cells. 2021;10(10)doi: 10.3390/cells10102750.
Ni, Z., & Cheng, X. (2021). Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis. Cells, 10(10), . https://doi.org/10.3390/cells10102750
Ni, Zhuofu, and Cheng, Xiaodong. "Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis." Cells vol. 10,10 (2021). doi: https://doi.org/10.3390/cells10102750
Ni Z, Cheng X. Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis. Cells. 2021 Oct 14;10(10). doi: 10.3390/cells10102750. PMID: 34685730; PMCID: PMC8534922.
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Cells. 2021 Oct 14;10(10). doi: 10.3390/cells10102750.

Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis.

Cells

Zhuofu Ni, Xiaodong Cheng

Affiliations

  1. Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  2. Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

PMID: 34685730 PMCID: PMC8534922 DOI: 10.3390/cells10102750

Abstract

Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are one of the several families of cellular effectors of the prototypical second messenger cAMP. To understand the origin and molecular evolution of EPAC proteins, we performed a comprehensive phylogenetic analysis of EPAC1 and EPAC2. Our study demonstrates that unlike its cousin PKA, EPAC proteins are only present in multicellular Metazoa. Within the EPAC family, EPAC1 is only associated with chordates, while EPAC2 spans the entire animal kingdom. Despite a much more contemporary origin, EPAC1 proteins show much more sequence diversity among species, suggesting that EPAC1 has undergone more selection and evolved faster than EPAC2. Phylogenetic analyses of the individual cAMP binding domain (CBD) and guanine nucleotide exchange (GEF) domain of EPACs, two most conserved regions between the two isoforms, further reveal that EPAC1 and EPAC2 are closely clustered together within both the larger cyclic nucleotide receptor and RAPGEF families. These results support the notion that EPAC1 and EPAC2 share a common ancestor resulting from a fusion between the CBD of PKA and the GEF from RAPGEF1. On the other hand, the two terminal extremities and the RAS-association (RA) domains show the most sequence diversity between the two isoforms. Sequence diversities within these regions contribute significantly to the isoform-specific functions of EPACs. Importantly, unique isoform-specific sequence motifs within the RA domain have been identified.

Keywords: EPAC1; EPAC2; cyclic nucleotide; guanine nucleotide exchange factor; phylogenetics

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