Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

Wheeler, Deric L.; Yarden, Yosef

doi:10.1007/978-1-4939-2053-2

Cited by 15 publications

(17 citation statements)

References 1,089 publications

(313 reference statements)

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“…Previously introduced, the diversity amongst receptor structures enable RTKs in responding to a wide array of extracellular cues-uniquely decoded into intracellular signals directing cell growth, differentiation, and function 215 . While conceptually straightforward, RTK signaling is complex, of which diverse biological processes involve a challenging amount of protein interactions 196,249 . The prototypical signaling network of the well-characterized EGFR family for instance, was determined to involve 122 proteins which form 211 different types of interactions 250 .…”

Section: -Rtk Signalingmentioning

confidence: 99%

“…Despite this complexity, extensive research on EGFR have provided useful insights in understanding RTK signaling topology. Specifically, biochemistry tools along with computational modeling have allowed systems biology in elucidating a "bow-tie" or "hourglass" network structure in describing RTK signaling 249 . Three sequential signaling layers make up this network model; the first layer consisting of broad input signals from ligands and multiple RTKs; the narrow second layer serving as the 'core processing' stage conserved amongst RTKs; and the broad third layer representing the diverse biological outputs of RTK signaling 249 .…”

Section: -Rtk Signalingmentioning

confidence: 99%

“…The first layer in the RTK bow-tie signaling topology consists of broad signaling input, derived from ligands and receptors which collectively induce RTK activation 11 . Specifically, the molecular diversity amongst ligands and receptors both contribute to distinct phosphorylation and hence, activation patterns of RTKs 249 . The input layer for EGFR activation for instance, primarily involve 11 ligands and four receptor types, of which individual parameters and ligand-receptor derivatives often drive distinct biological outcomes 11 .…”

Section: -The First Layer Of Rtk Signaling: Signal Inputmentioning

confidence: 99%

“…It is well understood that other RTK families utilize these canonical pathways with variations in location, intensity and duration 220,249 . Thus, although explicit in describing EGFR signaling, signaling properties of other RTK families may draw parallels from the following discussions; of key protein-protein interactions facilitating intracellular RTK network cascades.…”

Section: -The First Layer Of Rtk Signaling: Signal Inputmentioning

confidence: 99%

“…The third and final layer of the RTK 'bow-tie' network represents the diverse phenotypic output, derived from the summation of RTK-induced core processes 249 . At this stage, terminal effectors of signaling pathways induce gene transcription leading to diverse biological outputs, ranging from cell division and migration, to adhesion, differentiation, and apoptosis 244 .…”

Section: -The Third Layer Of Rtk Signaling: Signal Outputmentioning

confidence: 99%

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The effects of Mitogenic and Metabolic cues on clathrin-mediated endocytosis

Santos¹

2021

Preprint

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The cell ‘surfaceome’ collectively describes proteins found on the plasma membrane (PM), which functions in fundamental cellular processes including growth and proliferation. The surfaceome undergoes dynamic remodeling via the addition/removal of surface proteins in response to changing environmental conditions. In mammalian cells, surfaceome remodeling is predominantly facilitated by clathrin-mediated endocytosis (CME) which involves the invagination and internalization of PM regions via clathrin-coated structures—removing proteins from the cell surface. As a major regulator of the surfaceome, it is important to understand the underlying mechanisms governing CME, given that its dysregulation has been implicated in human pathologies including neurologic and oncogenic disorders. Cellular cues including mitogenic (e.g. growth factors) and metabolic signals (e.g. cellular energy levels) induce diverse cellular processes (e.g. growth and proliferation) requiring surfaceome/PM remodeling. Precisely how mitogenic and metabolic signals may induce surfaceome remodeling however, is under-examined. As a major regulator of the surfaceome, CME is a likely mechanism through which cellular cues may remodel the PM. Poorly understood, I thus sought to investigate how mitogenic and metabolic signals may regulate CME. Mitogenic signaling by the epidermal growth factor receptor (EGFR) triggers PLCγ1-calcium signals, which I found a requirement for CME of EGFR—likely via calcium control of the Sjn1 protein. Consistently, using TIRF-M imaging coupled to automated software analysis, I demonstrate that inhibition of PLCγ1-calcium signals impairs the formation/assembly of GFR-containing clathrin structures. In addition, I hypothesize that PLCγ1-calcium signals also regulates the CME of other surface proteins given its robust control of Sjn1—which localizes broadly amongst clathrin-coated structures. AMPK is a cellular energy sensor activated by metabolic stress (e.g. starvation). Using TIRF-M imaging coupled to automated software analysis, I found that AMPK activation broadly reduces the formation/assembly of bona fide clathrin-coated pits, without impairing the internalization rates of CME cargoes (e.g. EGFR, TfR and β1-integrin). Furthermore, I found that AMPK may regulate CME throughcontrol of the Arf6 protein. Collectively, my findings uncover and provide novel mechanisms by which mitogenic (via EGFR-induced calcium signals) and metabolic signals (via AMPK control of Arf6) may induce regulation of CME—in eliciting global reorganization of the plasma membrane. 1,2,11–13,3–10

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Section: -Rtk Signalingmentioning

confidence: 99%

Section: -Rtk Signalingmentioning

confidence: 99%

Section: -The First Layer Of Rtk Signaling: Signal Inputmentioning

confidence: 99%

Section: -The First Layer Of Rtk Signaling: Signal Inputmentioning

confidence: 99%

Section: -The Third Layer Of Rtk Signaling: Signal Outputmentioning

confidence: 99%

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The effects of Mitogenic and Metabolic cues on clathrin-mediated endocytosis

Santos¹

2021

Preprint

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CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance

Harris

Shi

Foster

et al. 2021

Sci Rep

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Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.

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Le récepteur de l’insuline a 50 ans – Revue des progrès accomplis

Meyts

2022

Biologie Aujourd’hui

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L’isolement de l’insuline du pancréas et sa purification à un degré suffisant pour permettre son administration à des patients atteints de diabète de type 1 furent accomplis il y a 100 ans à l’Université de Toronto par Banting, Best, Collip et McLeod et représentent sans conteste une des plus grandes révolutions thérapeutiques en médecine, reconnue par l’attribution du Prix Nobel de Physiologie ou Médecine en 1923 à Banting et McLeod. Les retombées cliniques furent rapides ainsi que l’internationalisation de sa production commerciale. Les retombées en matière de recherche fondamentale furent beaucoup plus lentes, en particulier en ce qui concerne les mécanismes moléculaires d’action de l’insuline sur ses cellules cibles. Presque un demi-siècle s’écoula avant la détermination de la structure tri-dimensionnelle de l’insuline en 1969 et la caractérisation de son récepteur cellulaire en 1970–1971. Le fait que le récepteur de l’insuline soit une enzyme appelée tyrosine kinase ne fut démontré que dans les années 1982–1985, et la structure cristallographique du domaine kinase intracellulaire fut déterminée dix ans plus tard. La structure cristallographique du premier substrat intracellulaire de la kinase (IRS-1) en 1991 ouvrira la voie à l’élucidation des voies de signalisation intracellulaires. Il faudra 15 ans de plus avant l’obtention de la structure cristallographique du domaine extracellulaire du récepteur (en l’absence d’insuline) en 2006. Depuis, la détermination de la structure du complexe insuline-récepteur dans les états inactif et activé a fait d’énormes progrès, en particulier grâce aux améliorations récentes dans les pouvoirs de résolution de la cryo-microscopie électronique. Je passerai ici en revue les étapes du développement du concept de récepteur hormonal, et de nos connaissances sur la structure et le mécanisme moléculaire d’activation du récepteur de l’insuline.

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Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease

Cited by 15 publications

References 1,089 publications

The effects of Mitogenic and Metabolic cues on clathrin-mediated endocytosis

The effects of Mitogenic and Metabolic cues on clathrin-mediated endocytosis

CD117/c-kit defines a prostate CSC-like subpopulation driving progression and TKI resistance

Le récepteur de l’insuline a 50 ans – Revue des progrès accomplis

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