Gamma-secretase-dependent signaling of receptor tyrosine kinases

Johannes A.M Merilahti,Klaus Elenius

doi:10.1038/s41388-018-0465-z

Johannes A.M Merilahti, Klaus Elenius

Open Access

https://doi.org/10.1038/s41388-018-0465-z

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Journal: Oncogene	Publication Date: Aug 30, 2018
Citations: 47	License type: open-access

Affiliation: University of Turku, Turku University Hospital

Abstract

Human genome harbors 55 receptor tyrosine kinases (RTK). At least half of the RTKs have been reported to be cleaved by gamma-secretase-mediated regulated intramembrane proteolysis. The two-step process involves releasing the RTK ectodomain to the extracellular space by proteolytic cleavage called shedding, followed by cleavage in the RTK transmembrane domain by the gamma-secretase complex resulting in release of a soluble RTK intracellular domain. This intracellular domain, including the tyrosine kinase domain, can in turn translocate to various cellular compartments, such as the nucleus or proteasome. The soluble intracellular domain may interact with transcriptional regulators and other proteins to induce specific effects on cell survival, proliferation, and differentiation, establishing an additional signaling mode for the cleavable RTKs. On the other hand, the same process can facilitate RTK turnover and proteasomal degradation. In this review we focus on the regulation of RTK shedding and gamma-secretase cleavage, as well as signaling promoted by the soluble RTK ICDs. In addition, therapeutic implications of increased knowledge on RTK cleavage on cancer drug development are discussed.

Highlights

Human genome harbors genes encoding 55 receptor tyrosine kinases (RTK) [1]
RTKs can signal through traditional, canonical pathways involving other kinases and lipid messengers but can signal through a noncanonical pathway involving the proteolytic release of intracellular domain fragments (ICD), which translocate to various cellular compartments [2–4]
Active RTK fragments can be generated by proteolytic cleavage resulting in the release of soluble RTK ICDs from the membrane

Summary

Introduction

Human genome harbors genes encoding 55 receptor tyrosine kinases (RTK) [1]. RTKs can signal through traditional, canonical pathways involving other kinases and lipid messengers but can signal through a noncanonical pathway involving the proteolytic release of intracellular domain fragments (ICD), which translocate to various cellular compartments [2–4].Full-length RTKs and RTK fragments have been observed in the intracellular cell compartments such as nucleus and mitochondria [4]. The ectodomain shedding is followed by the secondary cleavage event at the receptor transmembrane domain by gamma-secretase intramembrane protease complex, releasing an intracellular protein fragment (Fig. 1b). RTKs such as ERBB2 and TIE2 have been found to undergo ectodomain shedding, but no indications for gamma-secretase cleavage has been reported so far [22, 23].

Results

Conclusion