Send to

Choose Destination
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

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


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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center