Transmembrane Peptides as Inhibitors of Protein-Protein Interactions: An Efficient Strategy to Target Cancer Cells?

Camille Albrecht,Aline Appert-Collin,Laurent Duca,Béatrice Romier-Crouzet,Dominique Bagnard,Amar Bennasroune,Hervé Sartelet,Pascal Maurice,Sébastien Blaise,Roman G Efremov

doi:10.3389/fonc.2020.00519

Abstract

Cellular functions are regulated by extracellular signals such as hormones, neurotransmitters, matrix ligands, and other chemical or physical stimuli. Ligand binding on its transmembrane receptor induced cell signaling and the recruitment of several interacting partners to the plasma membrane. Nowadays, it is well-established that the transmembrane domain is not only an anchor of these receptors to the membrane, but it also plays a key role in receptor dimerization and activation. Indeed, interactions between transmembrane helices are associated with specific biological activity of the proteins as cell migration, proliferation, or differentiation. Overexpression or constitutive dimerization (due notably to mutations) of these transmembrane receptors are involved in several physiopathological contexts as cancers. The transmembrane domain of tyrosine kinase receptors as ErbB family proteins (implicated in several cancers as HER2 in breast cancer) or other receptors as Neuropilins has been described these last years as a target to inhibit their dimerization/activation using several strategies. In this review, we will focus on the strategy which consists in using peptides to disturb in a specific manner the interactions between transmembrane domains and the signaling pathways (induced by ligand binding) of these receptors involved in cancer. This approach can be extended to inhibit other transmembrane protein dimerization as neuraminidase-1 (the catalytic subunit of elastin receptor complex), Discoidin Domain Receptor 1 (a tyrosine kinase receptor activated by type I collagen) or G-protein coupled receptors (GPCRs) which are involved in cancer processes.

Highlights

Membrane proteins are defined as proteins found in cell membrane either at the surface or on intracellular organelles and represent around 30% of all eukaryotes and prokaryotes proteins
We will focus on the history of a strategy which consists of using peptides to disturb in a specific manner the interactions between TM domains and the signaling pathways induced by ligand binding of ErbB receptors and Neuropilins. This approach can be extended to inhibit other TM protein dimerization such as neuraminidase1 (Neu-1, the catalytic subunit of elastin receptor complex), DDR1 (Discoidin Domain Receptor 1, a receptor tyrosine kinase (RTK) activated by type I collagen) and G-protein coupled receptors (GPCRs) which are involved in cancer processes
Because TM peptides interact with intra-membrane targets, they do not have the capacity to be used to selectively reach the cancer cells expressing the target. They exert their function as small molecules by a widespread distribution in the body

Summary

INTRODUCTION

Membrane proteins are defined as proteins found in cell membrane either at the surface or on intracellular organelles and represent around 30% of all eukaryotes and prokaryotes proteins. The TM proteins (single or multi-pass membrane proteins) are involved in several cellular processes such as cell signaling, cell-cell communication, transport, energy transduction, and activation of enzymes which induce several functions like cell proliferation, migration, and differentiation These cellular responses are induced by external stimuli and mediated by signaling pathways activated by membrane receptors associated with a large panel of proteins constituting complex signal networks [3, 4]. This approach can be extended to inhibit other TM protein dimerization such as neuraminidase (Neu-1, the catalytic subunit of elastin receptor complex), DDR1 (Discoidin Domain Receptor 1, a RTK activated by type I collagen) and GPCRs which are involved in cancer processes. This part will describe the main results concerning the targeting of several membrane proteins involved in cancers by TM hydrophobic peptides which mimic the TM segments of these receptors

ErbB Receptor TM Domains as Targets in Cancer

Neuropilin and Plexin TM Domain as Targets in Cancers

GPCR TM Domain as a Putative Target in Cancers

CONCLUSION