Malha Sahmi

BRAF oncogenic mutants evade autoinhibition through a common mechanism

Hugo Lavoie, Ting Jin, Driss Lajoie, Marion Décossas et autres

Uncontrolled activation of the rat sarcoma (RAS)-extracellular signal-regulated kinase (ERK) pathway drives tumor growth, often because of oncogenic BRAF mutations. BRAF regulation, involving monomeric autoinhibition and activation by dimerization, has been intensely scrutinized, but mechanisms enabling oncogenic mutants to evade regulation remain …

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The CNK–HYP scaffolding complex promotes RAF activation by enhancing KSR–MEK interaction

Pierre Maisonneuve, Malha Sahmi, Fanny Bergeron-Labrecque, I. Xianjie et autres

The RAS-MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains …

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CNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling

Guillaume Serwe, David Kachaner, Jessica K. Gagnon, Cédric Plutoni et autres

Cell motility is a critical feature of invasive tumour cells that is governed by complex signal transduction events. Particularly, the underlying mechanisms that bridge extracellular stimuli to the molecular machinery driving motility remain partially understood. Here, we show that the scaffold protein …

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A putative protein–RNA complex regulates posttranscriptional processing of cytochrome P450 aromatase (CYP19A1) in bovine granulosa cells

Fatiha Sahmi, Malha Sahmi, Nicolas Y. Gévry, Pramod Sahadevan et autres

Follicle growth and granulosa cell health are dependent on the secretion of estradiol from granulosa cells. Estradiol is synthesized from androgen precursor by cytochrome P450 aromatase (CYP19A1), and in cattle CYP19A1 messenger RNA has a short half-life but a long (3.5 kb) …

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MEK drives BRAF activation through allosteric control of KSR proteins

Hugo Lavoie, Malha Sahmi, Pierre Maisonneuve, Sara A. Marullo et autres

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RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition

Ting Jin, Hugo Lavoie, Malha Sahmi, Maud David et autres

First-generation RAF inhibitors paradoxically induce ERK signaling in normal and tumor cells exhibiting RAS activity. Compound-induced RAF dimerization through stabilization of the RAF ON/active state by inhibitors has emerged as a critical contributing factor. RAF inhibitors also enhance RAS-RAF association. Although this …

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The Deubiquitinase USP47 Stabilizes MAPK by Counteracting the Function of the N-end Rule ligase POE/UBR4 in Drosophila

Dariel Ashton‐Beaucage, Caroline Lemieux, Christian M. Udell, Malha Sahmi et autres

RAS-induced MAPK signaling is a central driver of the cell proliferation apparatus. Disruption of this pathway is widely observed in cancer and other pathologies. Consequently, considerable effort has been devoted to understanding the mechanistic aspects of RAS-MAPK signal transmission and regulation. While …

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Apical Accumulation of the Sevenless Receptor Tyrosine Kinase During Drosophila Eye Development Is Promoted by the Small GTPase Rap1

Caroline Baril, Martin Lefrançois, Malha Sahmi, Helene Knævelsrud et autres

The Ras/MAPK-signaling pathway plays pivotal roles during development of metazoans by controlling cell proliferation and cell differentiation elicited, in several instances, by receptor tyrosine kinases (RTKs). While the internal mechanism of RTK-driven Ras/MAPK signaling is well understood, far less is known regarding …

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A Functional Screen Reveals an Extensive Layer of Transcriptional and Splicing Control Underlying RAS/MAPK Signaling in Drosophila

Dariel Ashton‐Beaucage, Christian M. Udell, Patrick Gendron, Malha Sahmi et autres

The small GTPase RAS is among the most prevalent oncogenes. The evolutionarily conserved RAF-MEK-MAPK module that lies downstream of RAS is one of the main conduits through which RAS transmits proliferative signals in normal and cancer cells. Genetic and biochemical studies conducted …

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A dimerization-dependent mechanism drives RAF catalytic activation

Thanashan Rajakulendran, Malha Sahmi, Martin Lefrançois, Frank Sicheri et autres

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The PP2C Alphabet Is a Negative Regulator of Stress-Activated Protein Kinase Signaling in Drosophila

Caroline Baril, Malha Sahmi, Dariel Ashton‐Beaucage, Beth E. Stronach et autres

The Jun N-terminal kinase and p38 pathways, also known as stress-activated protein kinase (SAPK) pathways, are signaling conduits reiteratively used throughout the development and adult life of metazoans where they play central roles in the control of apoptosis, immune function, and environmental …

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CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling

Thanashan Rajakulendran, Malha Sahmi, Igor V. Kurinov, Mike Tyers et autres

RAF kinase functions in the mitogen-activated protein kinase (MAPK) pathway to transmit growth signals to the downstream kinases MEK and ERK. Activation of RAF catalytic activity is facilitated by a regulatory complex comprising the proteins CNK (Connector enhancer of KSR), HYP (Hyphen), …

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