Reactome | PTK2 (FAK) and Gq/11 enhance the degradation of NFKBIA (IkBalpha), phosphorylation of RELA (p65) on serine-536, and translocation of p-S536-RELA:NFKB1 (p65:p50) to the nucleus

PTK2 (FAK) and Gq/11 enhance the degradation of NFKBIA (IkBalpha), phosphorylation of RELA (p65) on serine-536, and translocation of p-S536-RELA:NFKB1 (p65:p50) to the nucleus

Stable Identifier

R-HSA-9861486

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

cytosol, nucleoplasm

ReviewStatus

5/5

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PTK2 (FAK) and Gq/11 enhance the degradation of NFKBIA (IkBalpha), phosphorylation of RELA (p65) on serine-536, and translocation of p-S536-RELA:NFKB1 (p65:p50) to the nucleus

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Turbulent (disturbed) flow across endothelial cells activates NF-kB signaling by an incompletely characterized mechanism (Albarrán-Juárez et al. 2018, Nakayama et al. 2020). Canonical NF-kB signaling is initiated in the cytosol by IKK proteins (CHUK, IKBKB, IKBKE) which phosphorylate inhibitors, NFKBIA (IKBalpha) or IKBKB (IkBbeta), resulting in their ubiquitination and degradation. NF-kB transcription factor complexes such as RELA:NFKB1 (p65:p50) are then released to transit to the nucleus (reviewed in Zhang et al. 2017).
Unlike laminar flow, turbulent flow activates integrins, which activate PTK2 (FAK) and this together with Gq/11 G protein signaling are required for activation of NF-kB (Albarrán-Juárez et al. 2018, Nakayama et al. 2020). Gq/11 signaling may originate from activation of the P2RY2 purine receptor by ATP released from endothelial cells (Albarrán-Juárez et al. 2018). Activated (phosphorylated) PTK2 has been shown to phosphorylate the NF-KB activator CHUK (IKKalpha, IKKA) on tyrosines 187 and 198 and this phosphorylation enhances both canonical and non-canonical NF-KB signaling (Dwyer et al. 2015); however, the kinase specificities of p-Y187,Y198-CHUK were not profiled. PTK2 is not required for degradation of the NF-kB inhibitor NFKBIA (IkBalpha) (inferred from mouse and bovine cells in Petzold et al. 2009).
Phosphorylation of RELA on serine-536 is also observed in response to disturbed flow (Albarrán-Juárez et al. 2018, Nakayama et al. 2020, inferred from mouse and bovine cells in Petzold et al. 2009) and in response to acute early laminar flow (Chen et al. 2015). PIEZO1, P2RY2 (P2Y2), G alpha subunits Gq/11, and integrin ITGA5 are required for phosphorylation of serine-536 (Albarrán-Juárez et al. 2018). The IKK subunit IKBKB (IKKB, IKKbeta) is known to phosphorylate RELA on serine-536 (Sakurai et al. 1999, inferred from mouse homologs in Yang et al. 2003); however, this has not been demonstrated in endothelial cells exposed to disturbed flow (Yang et al. 2003). In TNF signaling, phosphorylation of RELA on serine-536 precedes, and is required for ubiquitination of CHUK (Hu et al. 2005).

Literature References

PubMed ID	Title	Journal	Year
25798060	Identification of novel focal adhesion kinase substrates: role for FAK in NFκB signaling Dwyer, SF, Gao, L, Gelman, IH	Int J Biol Sci	2015
33268595	Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis Nakayama, A, Albarrán-Juárez, J, Liang, G, Roquid, KA, Iring, A, Tonack, S, Chen, M, Müller, OJ, Weinstein, LS, Offermanns, S	JCI Insight	2020
30194266	Piezo1 and G_q/G₁₁ promote endothelial inflammation depending on flow pattern and integrin activation Albarrán-Juárez, J, Iring, A, Wang, S, Joseph, S, Grimm, M, Strilic, B, Wettschureck, N, Althoff, TF, Offermanns, S	J Exp Med	2018