RIPK4 activity in keratinocytes is controlled by the SCFβ-TrCP ubiquitin ligase to maintain cortical actin organization
2018
Tanghe, Giel | Urwyler-Rösselet, Corinne | De Groote, Philippe | Dejardin, Emmanuel | De Bock, Pieter-Jan | Gevaert, Kris | Vandenabeele, Peter | Declercq, Wim
RIPK4 is a key player in epidermal differentiation and barrier formation. RIPK4 signaling pathways controlling keratinocyte proliferation and differentiation depend on its kinase activity leading to Dvl2, Pkp1 and IRF6 phosphorylation and NF-κB activation. However, the mechanism regulating RIPK4 activity levels remains elusive. We show that cultured keratinocytes display constitutive active phosphorylated RIPK4 while PKC signaling can trigger RIPK4 activation in various non-keratinocyte cell lines, in which RIPK4 is present in a non-phosphorylated state. Interestingly, we identified the SCFᵝ⁻ᵀʳCᴾ ubiquitin E3 ligase complex responsible for regulating the active RIPK4 protein level. The SCFᵝ⁻ᵀʳCᴾ complex binds to a conserved phosphodegron motif in the intermediate domain of RIPK4, subsequently leading to K48-linked ubiquitinylation and degradation. The recruitment of β-TrCP is dependent on RIPK4 activation and trans-autophosphorylation. β-TrCP knock-down resulted in RIPK4-dependent formation of actin stress fibers, cell scattering and increased cell motility, suggesting that tight control of RIPK4 activity levels is crucial to maintain cell shape and behavior in keratinocytes.
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