Subversion of kindlin-3 function in PTEN null T-cell acute lymphoblastic leukemia

Kindlin-3 is an adapter protein that promotes cell adhesion and migration. Kindlin-3 binds phosphatidylinositol (3,4,5)-triphosphate (PIP3), which is a lipid product of PI3K that drives AKT signaling. The tumor suppressor PTEN phosphatase metabolizes and limits the level of PIP3. T-cell acute lymphoblastic leukemia (T-ALL) is a type of blood cancer that is highly aggressive. In pediatric T-ALL, PTEN-loss-of-function is a frequent occurrence that leads to dysregulated PIP3 turnover and aberrant AKT activation and signaling. Here we show for the first time that the function of kindlin-3 is subverted to promote Ras-B-Raf-MEK-ERK signaling in PTEN null T-ALL cells that does not require the binding of kindlin-3 to integrins. Mechanistically, we uncovered a novel preformed complex comprising kindlin-3, the scaffold protein RACK1 and MEK that is recruited to the PIP3-enriched plasma membrane via the pleckstrin homology (PH) domain of kindlin-3. This contributes to the assembly of B-Raf-MEK-ERK signaling components downstream of activated Ras. Consequently, the loss of kindlin-3 reduces ERK1/2 activation that dampens DNA damage response, leading to mitotic delay affecting cell proliferation. Taken together, our data show a central role of kindlin-3 in PTEN-null T-ALL progression.