The EphB6 Receptor: Kinase-Dead but Very Much Alive.

Timothy G Strozen, Jessica C Sharpe, Evelyn D Harris, Maruti Uppalapati, Behzad M Toosi

International journal of molecular sciences 2021 Jul 30

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The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, a greater appreciation for the role pseudoenzymes perform in expanding the repertoire of signals generated by signal transduction systems has fostered more interest in the field. EphB6 acts as a molecular switch that is capable of modulating the signal transduction output of Eph receptor clusters. Although the biological effects of EphB6 activity are well defined, the molecular mechanisms of EphB6 function remain enigmatic. In this review, we use a comparative approach to postulate how EphB6 acts as a scaffold to recruit adaptor proteins to an Eph receptor cluster and how this function is regulated. We suggest that the evolutionary repurposing of EphB6 into a kinase-independent molecular switch in mammals has involved repurposing the kinase activation loop into an SH3 domain-binding site. In addition, we suggest that EphB6 employs the same SAM domain linker and juxtamembrane domain allosteric regulatory mechanisms that are used in kinase-positive Eph receptors to regulate its scaffold function. As a result, although kinase-dead, EphB6 remains a strategically active component of Eph receptor signaling.

Citation

Timothy G Strozen, Jessica C Sharpe, Evelyn D Harris, Maruti Uppalapati, Behzad M Toosi. The EphB6 Receptor: Kinase-Dead but Very Much Alive. International journal of molecular sciences. 2021 Jul 30;22(15)