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Sci Rep. 2016 Sep 30;6:34349. doi: 10.1038/srep34349.

A pre-metazoan origin of the CRK gene family and co-opted signaling network.

Author information

1
The Ben May Department for Cancer Research, The University of Chicago, USA.
2
RIKEN Quantitative Biology Center (QBiC), Yokohama, Kanagawa, Japan.
3
RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan.
4
RIKEN Quantitative Biology Center (QBiC), Suita, Osaka, Japan.
5
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA.
6
Department of Evolutionary Studies of Biosystems, The Graduate University of Advanced Studies, Miura-gunn, Kanagawa, Japan.

Abstract

CRK and CRKL adapter proteins play essential roles in development and cancer through their SRC homology 2 and 3 (SH2 and SH3) domains. To gain insight into the origin of their shared functions, we have investigated their evolutionary history. We propose a term, crk/crkl ancestral (crka), for orthologs in invertebrates before the divergence of CRK and CRKL in the vertebrate ancestor. We have isolated two orthologs expressed in the choanoflagellate Monosiga brevicollis, a unicellular relative to the metazoans. Consistent with its highly-conserved three-dimensional structure, the SH2 domain of M. brevicollis crka1 can bind to the mammalian CRK/CRKL SH2 binding consensus phospho-YxxP, and to the SRC substrate/focal adhesion protein BCAR1 (p130CAS) in the presence of activated SRC. These results demonstrate an ancient origin of the CRK/CRKL SH2-target recognition specificity. Although BCAR1 orthologs exist only in metazoans as identified by an N-terminal SH3 domain, YxxP motifs, and a C-terminal FAT-like domain, some pre-metazoan transmembrane proteins include several YxxP repeats in their cytosolic region, suggesting that they are remotely related to the BCAR1 substrate domain. Since the tyrosine kinase SRC also has a pre-metazoan origin, co-option of BCAR1-related sequences may have rewired the crka-dependent network to mediate adhesion signals in the metazoan ancestor.

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