PLEKHH2 binds β-arrestin1 through its FERM domain, activates FAK/PI3K/AKT phosphorylation, and promotes the malignant phenotype of non-small cell lung cancer

Abstract

PLEKHH2 is an important FERM domain containing-protein. However, the role of PLEKHH2 in human solid tumors has not been reported yet. We report that PLEKHH2 showed enhanced cytoplasmic expression in non-small cell lung cancer (NSCLC). Its overexpression was positively correlated with high TNM stage, low differentiation, lymphatic node metastasis, and poor prognosis. In A549 and H1299 cells, high expression of PLEKHH2 significantly promoted cell proliferation, migration, invasion, and increased the expression of proliferation- and invasion-related proteins. It also enhanced the phosphorylation of FAK and promoted the activity of the PI3K/AKT pathway. Immunofluorescence and co-immunoprecipitation analyses were performed to elucidate the molecular mechanism underlying PLEKHH2-mediated regulation of proliferation and invasion in lung cancer cells. Upon transfection of full length PLEKHH2 or its FERM domain, we observed enhanced binding of PLEKHH2 to β-arrestin1, whereas FAK- β-arrestin1 binding was diminished and this led to an increase in FAK phosphorylation. PLEKHH2-mutant plasmids without the FERM domain could not effectively promote its binding to β-arrestin1, activation of FAK phosphorylation, PI3K/AKT activation, or the malignant phenotype. Our findings suggested that PLEKHH2 is an important oncogene in NSCLC. PLEKHH2 binding to β-arrestin1 through the FERM domain competitively inhibits β-arrestin1 binding to FAK, which causes the dissociation of FAK from the FAK-β-arrestin1 complex. Furthermore, the dissociation of FAK promotes its autophosphorylation, activates the PI3K/AKT signaling pathway, and subsequently promotes lung cancer cell proliferation, migration, and invasion. These results provide evidence for the potential use of PLEKHH2 inhibition as an anticancer therapy.

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

“…A recent study reported that PLEKHH2, a member of the pleckstrin homology domaincontaining family H, is also highly expressed in NSCLC (Wang et al, 2022b). Studies with NSCLC cells showed that high expression of PLEKHH2 facilitated cell proliferation, migration, and invasion (Wang et al, 2022b).…”

“…A recent study reported that PLEKHH2, a member of the pleckstrin homology domaincontaining family H, is also highly expressed in NSCLC (Wang et al, 2022b). Studies with NSCLC cells showed that high expression of PLEKHH2 facilitated cell proliferation, migration, and invasion (Wang et al, 2022b). Biochemical studies showed that PLEKHH2 binds to βarr1 through its FERM domain, resulting in the activation of the FAK/PI3K/AKT signaling cascade and the stimulation of NSCLC cell proliferation, migration, and invasion (Wang et al, 2022b).…”

Differential Effects of ABCG5/G8 Gene Region Variants on Lipid Profile, Blood Pressure Status, and Gallstone Disease History in Taiwan

“…Direct interactions between the FERM domain of the plekhh2 and the focal adhesion protein Hic-5 and actin stabilize the cortical actin cytoskeleton by attenuating actin depolymerization, and are involved in the podocyte foot processes [ 69 ]. A high expression of PLEKHH2 also significantly increased the expression of proliferation- and invasion-related proteins and promoted cell proliferation, migration, and invasion [ 70 ]. PLEKHH2 variants have been associated with diabetes nephropathy, coronary artery disease and venous thromboembolism, and have interacted with antihypertensive drugs for new-onset diabetes [ 71 , 72 , 73 , 74 ].…”

TGF-?/FAK/AKT Signal Pathway Blocked by Astragaloside, Hinders the Invasion and Metastasis of Non-Small Cell Lung Cancer

“…Furthermore, TGF-β has the ability to impact various intracellular signaling pathways, such as the VEGF and PI3K/AKT pathways, which play a crucial role in the proliferation, growth, and metastasis of lung cancer cells. They are effective therapeutic targets for lung cancer [19] . The findings indicated that the group B exhibited an increase in…”