RalB GTPase-Mediated Activation of the IκB Family Kinase TBK1 Couples Innate Immune Signaling to Tumor Cell Survival

Chien, Yuchen; Kim, Sung‐Chan; Bumeister, Ron; Loo, Yueh–Ming; Kwon, Sung Won; Johnson, Cynthia; Balakireva, Mirey G.; Roméo, Yves; Kopelovich, Levy; Gale, Michael; Yeaman, Charles; Camonis, Jacques; Zhao, Yingming; White, Michael A.

doi:10.1016/j.cell.2006.08.034

Cited by 350 publications

(413 citation statements)

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(84 reference statements)

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“…This regulation of vesicular trafficking controls various complex cellular functions such as polarized membrane formation, cytokinesis, tight junction formation, and tumor cell invasion [41][42][43][44] . RALB also interacts with Sec5 to activate the IκB kinase TBK1 [21,45] . Upon chronic RALB activation, the RALB/Sec5 effector complex, through TBK1, promotes cancer cell survival and RALB-mediated protection from apoptosis [45] .…”

Section: Ras Mutation and Cancer Therapeuticsmentioning

confidence: 99%

“…RALB also interacts with Sec5 to activate the IκB kinase TBK1 [21,45] . Upon chronic RALB activation, the RALB/Sec5 effector complex, through TBK1, promotes cancer cell survival and RALB-mediated protection from apoptosis [45] . A separate RALB/Exo84 complex activates autophagosome assembly under starvation conditions via ULK1 and Beclin1-VPS34 [21,46] .…”

Section: Ras Mutation and Cancer Therapeuticsmentioning

confidence: 99%

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The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

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Section: Ras Mutation and Cancer Therapeuticsmentioning

confidence: 99%

Section: Ras Mutation and Cancer Therapeuticsmentioning

confidence: 99%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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“…This was an interesting observation for 2 reasons. Firstly, Sec5 is known to accumulate in perinuclear endosomal compartments (Chien et al, 2006). Secondly, IFN production by Sendai virus involves the RALB and Sec5 pathways (Ross et al, 2006).…”

Section: Initial Characterization and Localization Of Stingmentioning

confidence: 99%

Binding of bacterial secondary messenger molecule c di-GMP is a STING operation

2012

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“…STAT3 and NF-kB not only cooperate as transcription factors, but STAT3-activating cytokines such as IL-6 are also NF-kB target genes. KRAS directly engages TBK1 via its downstream effector RALB, which further promotes NF-kB activation and drives CCL5 and IL-6 production together with IKKe [10,15,16]. IL-6 and STAT3 signaling also stimulate the expression of IKKe, unique among family members as an inducible IKK [17], which reinforces NF-kB activation and cytokine signaling downstream of KRAS.…”

Section: Cytokine Signal Transduction Networkmentioning

confidence: 99%