Disruption of the MST4‐pβ‐cateninThr40 axis in mice not only sharply decreased the number of ISCs/CSCs, but also suppressed CRC development; while constitutive activation of this axis by either forced activation of MST4 kinase or mutation of β‐catenin mimicking Thr40 phosphorylation led to increased number of ISCs/CSCs and exacerbated tumorigenesis. Here, STK26 is linked to colorectal carcinoma.