Background: Amotl2 is expressed in blood vessels, but its function in vasculature formation is unknown. Results: Amotl2 knockdown impairs intersegmental vessel growth in zebrafish embryos and in vitro tube formation of human endothelial cells. Conclusion: Amotl2 is required for angiogenesis by regulating cell polarity, migration, and proliferation in a way related to MAPK activation. Significance: Amotl2 plays important roles in regulating multiple behaviors of endothelial cells during angiogenesis.

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<div>Abstract<p>Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., <i>FAT1</i>, <i>PTEN</i>, or <i>ARID1A</i> loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18^INK4C). <i>In vitro</i> binding and kinase assays together with physical modeling reveal that the p18^INK4C–cyclin D–CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects <i>in vivo</i>, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance.</p>Significance:<p>CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6–INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.</p><p><i>This article is highlighted in the In This Issue feature, p. 275</i></p></div>