The EphB6 Receptor: Kinase-Dead but Very Much Alive
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 g...
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doaj-b70b0c5a471347da833ccbcd5a7979462021-08-06T15:25:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-01228211821110.3390/ijms22158211The EphB6 Receptor: Kinase-Dead but Very Much AliveTimothy G. Strozen0Jessica C. Sharpe1Evelyn D. Harris2Maruti Uppalapati3Behzad M. Toosi4Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, CanadaDepartment of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, CanadaDepartment of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, CanadaDepartment of Pathology and Lab Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, CanadaThe 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.https://www.mdpi.com/1422-0067/22/15/8211Eph receptorspseudokinasekinase-independent functionsscaffoldSH2 and SH3 domain binding |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Timothy G. Strozen Jessica C. Sharpe Evelyn D. Harris Maruti Uppalapati Behzad M. Toosi |
spellingShingle |
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 Eph receptors pseudokinase kinase-independent functions scaffold SH2 and SH3 domain binding |
author_facet |
Timothy G. Strozen Jessica C. Sharpe Evelyn D. Harris Maruti Uppalapati Behzad M. Toosi |
author_sort |
Timothy G. Strozen |
title |
The EphB6 Receptor: Kinase-Dead but Very Much Alive |
title_short |
The EphB6 Receptor: Kinase-Dead but Very Much Alive |
title_full |
The EphB6 Receptor: Kinase-Dead but Very Much Alive |
title_fullStr |
The EphB6 Receptor: Kinase-Dead but Very Much Alive |
title_full_unstemmed |
The EphB6 Receptor: Kinase-Dead but Very Much Alive |
title_sort |
ephb6 receptor: kinase-dead but very much alive |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-07-01 |
description |
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. |
topic |
Eph receptors pseudokinase kinase-independent functions scaffold SH2 and SH3 domain binding |
url |
https://www.mdpi.com/1422-0067/22/15/8211 |
work_keys_str_mv |
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