More than the sum of the parts: Toward full‐length receptor tyrosine kinase structures

Abstract

Intercellular communication governs complex physiological processes ranging from growth and development to the maintenance of cellular and organ homeostasis. In nearly all metazoans, receptor tyrosine kinases (RTKs) are central players in these diverse and fundamental signaling processes. Aberrant RTK signaling is at the root of many developmental diseases and cancers and it remains a key focus of targeted therapies, several of which have achieved considerable success in patients. These therapeutic advances in targeting RTKs have been propelled by numerous genetic, biochemical, and structural studies detailing the functions and molecular mechanisms of regulation and activation of RTKs. The latter in particular have proven to be instrumental for the development of new drugs, selective targeting of mutant forms of RTKs found in disease, and counteracting ensuing drug resistance. However, to this day, such studies have not yet yielded high‐resolution structures of intact RTKs that encompass the extracellular and intracellular domains and the connecting membrane‐spanning transmembrane domain. Technically challenging to obtain, these structures are instrumental to complete our understanding of the mechanisms by which RTKs are activated by extracellular ligands and of the effect of pathological mutations that do not directly reside in the catalytic sites of tyrosine kinase domains. In this review, we focus on the recent progress toward obtaining such structures and the insights already gained by structural studies of the subdomains of the receptors that belong to the epidermal growth factor receptor, insulin receptor, and platelet‐derived growth factor receptor RTK families. © 2019 IUBMB Life, 71(6):706–720, 2019

EGFR forms ligand-independent oligomers that are distinct from the active state

“…The mechanism for this autoinhibition remains incompletely understood, however. In contrast, much is known about how ligand binding promotes ERBB activation (31,32). In the absence of ligand, the EGFR, ERBB3, and ERBB4 ECDs adopt a tethered conformation that buries an extended beta-hairpin loop (33)(34)(35)(36).…”

Cell Communications among Microorganisms, Plants, and Animals: Origin, Evolution and Interplays

“…channel-receptors letting in specific ions [111,112]; receptors acting by direct catalysis (receptors with intrinsic enzymatic activity, i.e. protein kinase activity [113,114], or phosphatase activity [115], or guanylate cyclase activity [116,117]) ; receptors acting through recruitment of various downstream intracellular effectors (G proteins [118][119][120][121][122][123][124][125], adenylate cyclases [126][127][128], phospholipases C [129][130][131], soluble protein kinases [132][133][134][135][136][137], methyltransferases [138], proteases [139][140][141][142]…”

Cell Communications among Microorganisms, Plants, and Animals: Origin, Evolution and Interplays

“…channel-receptors letting in specific ions [118,119]; receptors acting by direct catalysis (receptors with intrinsic enzymatic activity, i.e. protein kinase activity [120,121], or phosphatase activity [122], or guanylate cyclase activity [123,124]; receptors acting through recruitment of various downstream intracellular effectors (G proteins [125][126][127][128][129][130][131][132], adenylate cyclases [133][134][135], phospholipases C [136][137][138], soluble protein kinases [139][140][141][142][143][144], methyltransferases [145], proteases [146][147][148][149] downstream partners are generally concentrated at the level of lipid rafts [150] or primary cilium in metazoan [84,151]. The downstream signaling pathways and their evolution have been thoroughly described in a recent comprehensive review [152] Many hormones are released in a pulsatile manner, and the frequency of their pulsatile secretion often governs the efficacy of their signaling.…”