The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan

Abstract

Tyrosine kinase signaling has long been considered a hallmark of intercellular communication, unique to multicellular animals. Our genomic analysis of the unicellular choanoflagellate Monosiga brevicollis discovers a remarkable count of 128 tyrosine kinases, 38 tyrosine phosphatases, and 123 phosphotyrosine (pTyr)-binding SH2 proteins, all higher counts than seen in any metazoan. This elaborate signaling network shows little orthology to metazoan counterparts yet displays many innovations reminiscent of metazoans. These include extracellular domains structurally related to those of metazoan receptor kinases, alternative methods for membrane anchoring and phosphotyrosine interaction in cytoplasmic kinases, and domain combinations that link kinases to small GTPase signaling and transcription. These proteins also display a wealth of combinations of known signaling domains. This uniquely divergent and elaborate signaling network illuminates the early evolution of pTyr signaling, explores innovative ways to traverse the cellular signaling circuitry, and shows extensive convergent evolution, highlighting pervasive constraints on pTyr signaling.

Fig. 1.

Phylogenetic tree of Monosiga tyrosine kinases, based on alignment of kinase domains, pairwise similarity, and conservation of key residues. Second kinase domains are prefixed by b-. Specific branching patterns between most families are relatively poorly supported.

Fig. 2.

Domain architecture of representative tyrosine kinases. Predicted inactive kinase domains indicated by lightning bolt, fragments or partial matches to domains indicated by shortened icons. SigP: signal peptide; Myr, myristoylation site; other names from Pfam, SMART, or Table S1. For fuller tyrosine kinome, see Fig. S1 and http://kinase.com/kinbase.

Fig. 3.

Monosiga Src1 kinase efficiently phosphorylates two RM2 motifs in the cytoplasmic tail of RTKB2 (MbRTK1). The higher efficiency relative to a site on a Monosiga STAT homolog or a consensus c-Src substrate suggests that these are specific Src1 phosphorylation sites.

Fig. 4.

Domain organization of selected PTP, PTB and SH2 domain-containing proteins. For fuller details, see Fig. S2 and http://kinase.com/kinbase.