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 SCF ubiquitin E3 ligase complex responsible for regulating the active RIPK4 protein level. The SCF 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.