GPCRs in Cancer: Protease-Activated Receptors, Endocytic Adaptors and Signaling.

Joann Trejo,Aleena Arakaki,Wen-An Pan

doi:10.3390/ijms19071886

Joann Trejo, Aleena Arakaki + Show 1 more

Open Access

https://doi.org/10.3390/ijms19071886

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Abstract

G protein-coupled receptors (GPCRs) are a large diverse family of cell surface signaling receptors implicated in various types of cancers. Several studies indicate that GPCRs control many aspects of cancer progression including tumor growth, invasion, migration, survival and metastasis. While it is known that GPCR activity can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, and increased production and secretion of agonists, the precise mechanisms of how GPCRs contribute to cancer progression remains elusive. Protease-activated receptors (PARs) are a unique class of GPCRs implicated in cancer. PARs are a subfamily of GPCRs comprised of four members that are irreversibly activated by proteolytic cleavage induced by various proteases generated in the tumor microenvironment. Given the unusual proteolytic irreversible activation of PARs, expression of receptors at the cell surface is a key feature that influences signaling responses and is exquisitely controlled by endocytic adaptor proteins. Here, we discuss new survey data from the Cancer Genome Atlas and the Genotype-Tissue Expression projects analysis of expression of all PAR family member expression in human tumor samples as well as the role and function of the endocytic sorting machinery that controls PAR expression and signaling of PARs in normal cells and in cancer.

Highlights

G protein-coupled receptors (GPCRs) are a large and diverse family of signaling receptors that function in cancer growth and development by regulating cellular proliferation, invasion, migration, immune cell-mediated functions, angiogenesis and survival at metastatic sites [1,2,3]
We showed that activation of a ubiquitin-deficient PAR1 mutant sorted directly to intraluminal vesicles (ILVs) of multivesicular bodies (MVBs)/lysosomes and degraded similar to wildtype receptor (Figure 4) [38,82], and raised the question of how a GPCR can be targeted to lysosomes for degradation independent of ubiquitination
Consistent with this idea, we found that ALG-2-interacting protein X (ALIX) activity is regulated through agonist-activated PAR1 stimulated signaling that leads to WWP2-mediated ubiquitination of ALIX, dimerization and enhanced activity at sorting PAR1 to MVBs/lysosomes (Figure 4) [103]

Summary

Introduction

G protein-coupled receptors (GPCRs) are a large and diverse family of signaling receptors that function in cancer growth and development by regulating cellular proliferation, invasion, migration, immune cell-mediated functions, angiogenesis and survival at metastatic sites [1,2,3]. Several GPCRs have been implicated in metastatic cancer, including the unique family of protease-activated receptor (PARs). While activated PAR2 signals through heterotrimeric G proteins at the plasma membrane, signaling is further propagated at endosomes through PAR2-β-arrestin-dependent activation of MAP kinases [18,19]. Dysregulation of these signaling events may lead to increased tumorigenesis, invasion and metastasis. We discuss a survey of PAR family member expression from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx) in human tumor samples in various cancer types, using a newly developed online platform, Gene Expression Profiling Interactive Analysis (GEPIA) [20] as well as the different endocytic mechanisms that control PAR expression and signaling

PAR Expression in Human Cancer

Internalization and Recycling of PARs and Implications in Cancer

Lysosomal Sorting of PARs and Dysregulation in Cancer

PAR2 Lysosomal Sorting Requires Ubiquitination and Canonical ESCRT

Findings

Conclusions