Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Tulpule, Asmin; Guan, Juan; Neel, Dana S.; Allegakoen, Hannah R.; Lin, Yone Phar; Brown, David; Chou, Yu-Ting; Heslin, Ann; Chatterjee, Nilanjana; Perati, Shriya; Menon, Shruti; Nguyen, Tracy; Debnath, Jayanta; Ramirez, Alexander; Shi, Xiaoyu; Yang, Bin; Feng, Siyu; Makhija, Suraj; Huang, Bo; Bivona, Trever G.

doi:10.1016/j.cell.2021.03.031

Cited by 106 publications

(71 citation statements)

References 59 publications

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“…The major characteristics of LLPS foci are that they: (i) fuse after touching and revert into a spherical shape; (ii) deform, diffuse and exchange material with the cytoplasm; (iii) adopt a spherical shape that is driven by surface tension; and (iv) recover rapidly through internal rearrangement and cytoplasmic exchange when photobleached (Hyman et al , 2014 ). Recently, Tulpule and colleagues have observed RTK fusion proteins, including EML4‐ALK V1 and V3, forming membraneless cytoplasmic granules that act as centres for the organisation and activation of RAS and other downstream signalling pathway components (Tulpule et al , 2021 ). Intriguingly, the granules are disrupted by a catalytically inactive mutant leading to the hypothesis that their formation is dependent on ALK activity (Tulpule et al , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Tulpule and colleagues have observed RTK fusion proteins, including EML4‐ALK V1 and V3, forming membraneless cytoplasmic granules that act as centres for the organisation and activation of RAS and other downstream signalling pathway components (Tulpule et al , 2021 ). Intriguingly, the granules are disrupted by a catalytically inactive mutant leading to the hypothesis that their formation is dependent on ALK activity (Tulpule et al , 2021 ). Despite the recent progress made to understand the functional role of EML4‐ALK foci in oncogenic signalling, the molecular interactions that underpin their formation are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Phase‐separated foci of EML4‐ALK facilitate signalling and depend upon an active kinase conformation

et al. 2021

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Variants of the oncogenic EML4‐ALK fusion protein contain a similar region of ALK encompassing the kinase domain, but different portions of EML4. Here, we show that EML4‐ALK V1 and V3 proteins form cytoplasmic foci that contain components of the MAPK, PLCγ and PI3K signalling pathways. The ALK inhibitors ceritinib and lorlatinib dissolve these foci and EML4‐ALK V3 but not V1 protein re‐localises to microtubules, an effect recapitulated in a catalytically inactive EML4‐ALK mutant. Mutations that promote a constitutively active ALK stabilise the cytoplasmic foci even in the presence of these inhibitors. In contrast, the inhibitor alectinib increases foci formation of both wild‐type and catalytically inactive EML4‐ALK V3 proteins, but not a Lys‐Glu salt bridge mutant. We propose that EML4‐ALK foci formation occurs as a result of transient association of stable EML4‐ALK trimers mediated through an active conformation of the ALK kinase domain. Our results demonstrate the formation of EML4‐ALK cytoplasmic foci that orchestrate oncogenic signalling and reveal that their assembly depends upon the conformational state of the catalytic domain and can be differentially modulated by structurally divergent ALK inhibitors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase‐separated foci of EML4‐ALK facilitate signalling and depend upon an active kinase conformation

et al. 2021

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“…Besides, Tulpule et al [ 47 ] demonstrated that RTK fusion oncoproteins can form membraneless intracellular protein granules. An array of RTK adaptor and effector molecules and RAS activating proteins are identified at the biomolecular condensates, including GAB1, GRAB2, SHP2, and SOS1.…”

Section: Mechanisms Of Fgfr Fusion Oncoproteinmentioning

confidence: 99%

“…4 B). Interestingly, the cytoplasmic granule formation may be a general mechanism for oncogenic RTK-mediated signaling activation by FGFR [ 47 ]. Thus, drugs to disrupt the nucleation of FGFR membraneless cytoplasmic protein granules may provide opportunities for the treatment of FGFR oncoprotein-driven cancers.…”

Section: Mechanisms Of Fgfr Fusion Oncoproteinmentioning

confidence: 99%

Fibroblast growth factor receptor fusions in cancer: opportunities and challenges

Chen

Zhang

Yin

et al. 2021

J Exp Clin Cancer Res

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Fibroblast growth factors (FGFs) and their receptors (FGFRs) play critical roles in many biological processes and developmental functions. Chromosomal translocation of FGFRs result in the formation of chimeric FGFR fusion proteins, which often cause aberrant signaling leading to the development and progression of human cancer. Due to the high recurrence rate and carcinogenicity, oncogenic FGFR gene fusions have been identified as promising therapeutic targets. Erdafitinib and pemigatinib, two FGFR selective inhibitors targeting FGFR fusions, have been approved by the U.S. Food and Drug Administration (FDA) to treat patients with urothelial cancer and cholangiocarcinoma, respectively. Futibatinib, a third-generation FGFR inhibitor, is under phase III clinical trials in patients with FGFR gene rearrangements. Herein, we review the current understanding of the FGF/FGFRs system and the oncogenic effect of FGFR fusions, summarize promising inhibitors under clinical development for patients with FGFR fusions, and highlight the challenges in this field.

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“…K-Ras4B is an excellent example of a small GTPase that relies primarily on membrane localization for its activity ( Cox et al, 2015 ; Kattan and Hancock, 2020 ; Uprety and Adjei, 2020 ). However, recent studies indicate that under certain conditions, K-Ras4B might participate in signaling complexes that are not associated with membranes ( Tulpule et al, 2021 ). Some small GTPases are known to be activated at sites other than membranes.…”

Section: Introductionmentioning

confidence: 99%

SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

Brandt

Koehn

Williams

2021

Front. Mol. Biosci.

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Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. SmgGDS-607 binds pre-prenylated small GTPases, while SmgGDS-558 binds prenylated small GTPases. This review discusses the history of SmgGDS research and explains our current understanding of how SmgGDS splice variants regulate the prenylation and trafficking of small GTPases. We discuss recent evidence that mutant forms of RabL3 and Rab22a control the release of small GTPases from SmgGDS, and review the inhibitory actions of DiRas1, which competitively blocks the binding of other small GTPases to SmgGDS. We conclude with a discussion of current strategies for therapeutic targeting of SmgGDS in cancer involving splice-switching oligonucleotides and peptide inhibitors.

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Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Cited by 106 publications

References 59 publications

Phase‐separated foci of EML4‐ALK facilitate signalling and depend upon an active kinase conformation

Phase‐separated foci of EML4‐ALK facilitate signalling and depend upon an active kinase conformation

Fibroblast growth factor receptor fusions in cancer: opportunities and challenges

SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

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