CKII-Phosphorylated HPV-16 E7 Disrupts Planar Cell Polarity by Recruiting Vangl1
Gbala, I. D.; Basukala, O.; Myers, M. P.; Bertolio, R.; Del Sal, G.; Banks, L.
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High-risk human papillomaviruses (HPVs) depend on continuous expression of the E6 and E7 oncoproteins to sustain malignant transformation. The high-risk E7 oncoprotein is multifunctional, and its phosphorylation by Casein Kinase II (CKII) amplifies its oncogenic potential. Here, we identify Vangl1, a core planar cell polarity (PCP) scaffold protein, as a novel, phosphorylation-dependent interactor of HPV-16 E7. CKII-mediated phosphorylation is required for Vangl1 recruitment, and this interaction is largely selective for HPV-16 E7. In cervical cancer cells, E7 expression profoundly disrupts Vangl1 homeostasis, producing a biphasic proteostatic imbalance in which phosphorylated Vangl1 is aberrantly retained. This retention parallels E7 stability, revealing a reciprocal oncogenic stabilization. E7 also impairs Vangl1 trafficking and localization by co-opting the clathrin adaptor subunit AP1M1. Functionally, Vangl1 depletion mirrors E6/E7 loss in CaSki spheroids by disrupting spheroid architecture, reducing invasiveness, and increasing chemosensitivity. Taken together, these findings position Vangl1 as a central effector in E7-mediated cervical transformation and invasive progression. TeaserE7s control of Vangl1 reveals a polarity-remodeling mechanism that drives cervical cancer invasion and progression.
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