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Editorial
. 2019 Feb 1;9(2):449-454.
eCollection 2019.

SHEDding light on the role of Pragmin pseudo-kinases in cancer

Serge Roche  1 , Céline Lecointre  1 , Valérie Simon  1 , Gilles Labesse  2
Affiliations
Editorial

SHEDding light on the role of Pragmin pseudo-kinases in cancer

Serge Roche et al. Am J Cancer Res. .

Abstract

The human kinome comprises more than 50 pseudo-kinases with unclear biological function due to the absence of apparent catalytic activity, and therefore, with presumably little interest for cancer drug discovery. However, it is now acknowledged that several of them, such as Pragmin family members, play roles as important as those of active kinases in human cancer. How these pseudo-kinases promote tumor formation is largely unknown. Recently, independent structural analyses of three Pragmin pseudo-kinases (Pragmin, SGK223, and SGK269/PEAK1) revealed a split helical dimerization (SHED)-based mechanism of action. Additional sequence-structure analysis identified C19orf35 as a new member of the Pragmin family. Based on the results of these molecular studies, we present a unified model on how Pragmin pseudo-kinases may regulate oncogenic signaling, and suggest potential therapeutic strategies to block their tumor activity.

Keywords: Pseudo-kinase; cancer; cell growth; cell migration; cell signaling; phosphorylation; structure; therapeutic target.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Proposed tumor activity of Pragmin pseudo-kinases. Integrins and growth factor receptors induce pseudo-kinase activation by a double-act mechanism (see Figure 3) enhancing MAPKs, Jak/Stat3, Notch, ZEB1, YAP/TAZ and Rho-pathways to induce gene expression and cytoskeleton rearrangement necessary for tumor cell growth and migration.
Figure 2
Figure 2
The growing family of Pragmin pseudo-kinases. Modular structure of Pragmin pseudo-kinases with the associated activated protein kinase shown in red. The modular structure of the closest active protein kinase homolog PINK1 is also shown. Predicted additional regulatory mechanisms are highlighted by question marks.
Figure 3
Figure 3
A double-act mechanism for Pragmin pseudo-kinase signaling in human cancer. SHED-mediated pseudo-kinase dimerization activates the associated protein tyrosine kinase upon tyrosine phosphorylation by upstream signals to phosphorylate specific cancer substrates.
See this image and copyright information in PMC

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