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.
Highlights
The oncogene v-CRK was originally identified in CT10 avian sarcoma virus
Our studies demonstrate that the CRK/CRKL ancestral gene evolved before the divergence of the metazoan ancestor, and that the SRC homology 2 (SH2) domain of the CRK/CRKL ancestral protein already had the ability to recognize YxxP motifs, an SH2 binding consensus initially discovered with human CRK30
Based on the refined sequence information we obtained, our analysis suggests that the divergence of vertebrate crk and crkl genes may have taken place at or before the divergence of the vertebrate ancestor
Summary
The oncogene v-CRK was originally identified in CT10 avian sarcoma virus. Despite the fact that CRK does not encode a tyrosine kinase, v-CRK can increase phosphotyrosine contents in the cell[1]. Overexpression of CRK or CRKL has been linked to a subset of some cancer types such as ovarian and non-small cell lung cancer[4]. One can hypothesize that while functional and structural differences likely resulted from co-option upon their divergence, their shared functions were inherited from their common ancestral gene during evolution Both CRK and CRKL encode adapter proteins consisting of an N-terminal SRC homology 2 (SH2) domain followed by two SH3 domains, SH3n and SH3c1. Unlike SH3n, SH3c is a non-canonical SH3 domain that does not bind proline-rich targets[4] Through these domains, CRK and CRKL can relay PTK-activated signals to downstream signaling mediators, and regulate cell proliferation, migration, and adhesion in response to growth factors as well as cell-matrix interactions[4]. Since communications between the cell and extracellular matrix are vital in multicellular organisms, one important question is how intracellular signaling components have become an integral part of cell-matrix adhesions in the signaling network during pre and post-metazoan evolution
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