Mechanistic principles of RAF kinase signaling

Udell, Christian M.; Rajakulendran, Thanashan; Sicheri, Frank; Therrien, Marc

doi:10.1007/s00018-010-0520-6

Cited by 66 publications

(73 citation statements)

References 158 publications

(226 reference statements)

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“…Additional pathway complexity arises from its lack of linearity, as BRAF can form a heterodimer with CRAF, resulting in downstream MEK-ERK signaling (6,7), which can also occur even when one of the heterodimers is inactive. Additionally, kinase suppressor of Ras (KSR), which functions primarily as a scaffold, colocalizing Raf, Mek, and Erk, is able to trigger BRAF activation through side-to-side heterodimerization (8,9). Thus, the intricacy of the MAPK pathway and the regulation of BRAF within it create a variety of opportunities whereby a mutation could result in aberrant BRAF signaling.…”

Section: Introductionmentioning

confidence: 99%

Role of BRAF in Thyroid Oncogenesis

Caronia

Phay²,

Shah³

2011

Clinical Cancer Research

107

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BRAF, a cytoplasmic serine-threonine protein kinase, plays a critical role in cell signaling as an activator within the mitogen-activated protein kinase (MAPK) pathway. The most common BRAF mutation is the V600E transversion, which causes constitutive kinase activity. This mutation has been found in a multitude of human cancers, including both papillary thyroid cancer (PTC) and papillary-derived anaplastic thyroid cancer (ATC), in which it initiates follicular cell transformation. With such a high frequency of BRAF mutations in PTC (44%)

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Section: Introductionmentioning

confidence: 99%

Role of BRAF in Thyroid Oncogenesis

Caronia

Phay²,

Shah³

2011

Clinical Cancer Research

107

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“…Raf binds to the effector region of GTP-Ras, which is the first signal to recruit cytosolic Raf to the plasma membrane. As a consequence, 14-3-3 protein is released from the N-terminal region of Raf, which liberates its autoinhibitory closed conformation (26,27). Moreover, homo-or heterodimerization of the Raf kinases is a crucial step in Raf activation.…”

mentioning

confidence: 99%

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

Siljamäki

Abankwa

2016

Molecular and Cellular Biology

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The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is tightly controlled by negative feedback regulators, such as the tumor suppressor SPRED1. The SPRED1 gene also carries loss-of-function mutations in the RASopathy Legius syndrome. Growth factor stimulation translocates SPRED1 to the plasma membrane, triggering its inhibitory activity. However, it remains unclear whether SPRED1 there acts at the level of Ras or Raf. We show that pharmacological or galectin-1 (Gal-1)-mediated induction of B-and C-Raf-containing dimers translocates SPRED1 to the plasma membrane. This is facilitated in particular by SPRED1 interaction with B-Raf and, via its N terminus, with Gal-1. The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. On the plasma membrane, SPRED1 becomes enriched in acidic membrane domains to specifically perturb membrane organization and extracellular signal-regulated kinase (ERK) signaling of active K-ras4B (here, K-ras) but not H-ras. However, SPRED1 also blocks on the nanoscale the positive effects of Gal-1 on H-ras. Therefore, a combinatorial expression of SPRED1 and Gal-1 potentially regulates specific patterns of K-ras-and H-ras-dependent signaling output. More broadly, our results open up the possibility that related SPRED and Sprouty proteins act in a similar Ras and Raf isoform-specific manner.S PRED (Sprouty-related proteins with an EVH1 domain) proteins are Sprouty-related negative modulators of Ras/mitogen-activated protein kinase (MAPK) signaling, and they have been shown to attenuate extracellular signal-regulated kinase (ERK) activity following various extracellular mitogenic stimuli (e.g., growth factors, cytokines, and chemokines) (1-5). The mammalian SPRED family contains four members, SPRED1, SPRED2, SPRED3, and Eve-3, the last of which is a splice variant of SPRED3 (1, 2, 6). SPRED1 and SPRED2 proteins contain an N-terminal enabled/vasodilator-stimulated phosphoprotein homology-1 (EVH1) domain and a cysteine-rich C-terminal Sprouty-related (SPR) domain, separated by a small c-Kit-binding domain (KBD) (2, 7). The SPR domain is necessary for membrane anchoring following growth factor stimulation (5), and both EVH1 and SPR domains have been implicated in ERK suppression (5,8,9). SPRED3 lacks a functional KBD and shows lower inhibitory activity than SPRED1 and -2, suggesting that the KBD also participates in inhibiting ERK activity (1-5).The precise mechanism of action of how SPRED proteins block MAPK signaling remains unclear. Overexpression of SPRED1 was suggested to increase the recruitment of the Ras effector Raf to the plasma membrane, where its association with Ras does not, however, lead to Raf activation (1, 2, 6). Instead, SPRED1 was reported to prolong Ras-Raf complexation, thus withdrawing Raf from activation by phosphorylation (2, 7). Another study showed that overexpression of SPRED1 inhibits Ras activation, as evidenced by decreased levels of GTP-bound ...

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“…Kinase Suppressor of Ras (KSR) is one of these and corresponds to a pseudokinase related to RAF family kinases (Therrien et al 1995). KSR has the ability to bridge RAF and MEK together as well as to drive the catalytic activation of RAF through heterodimerization of their respective kinase domain (Udell et al 2011).…”

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confidence: 99%

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

et al. 2014

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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 its interplay with other corequired signaling events involved in developmental decisions. In a genetic screen designed to identify new regulators of RTK/Ras/MAPK signaling during Drosophila eye development, we identified the small GTPase Rap1, PDZ-GEF, and Canoe as components contributing to Ras/MAPK-mediated R7 cell differentiation. Rap1 signaling has recently been found to participate in assembling cadherin-based adherens junctions in various fly epithelial tissues. Here, we show that Rap1 activity is required for the integrity of the apical domains of developing photoreceptor cells and that reduced Rap1 signaling hampers the apical accumulation of the Sevenless RTK in presumptive R7 cells. It thus appears that, in addition to its role in cell-cell adhesion, Rap1 signaling controls the partitioning of the epithelial cell membrane, which in turn influences signaling events that rely on apico-basal cell polarity.

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Mechanistic principles of RAF kinase signaling

Cited by 66 publications

References 158 publications

Role of BRAF in Thyroid Oncogenesis

Role of BRAF in Thyroid Oncogenesis

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

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

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