Loss of ASAP1 in mice impairs adipogenic and osteogenic differentiation of mesenchymal progenitor cells through dysregulation of FAK/Src and AKT signaling.

ASAP1 is a multi-domain adaptor protein that regulates cytoskeletal dynamics, receptor recycling and intracellular vesicle trafficking. Its expression is associated with poor prognosis for a variety of cancers, and promotes cell migration, invasion and metastasis. Little is known about its physiological role. In this study, we used mice with a gene-trap inactivated ASAP1 locus to study the functional role of ASAP1 in vivo, and found defects in tissues derived from mesenchymal progenitor cells. Loss of ASAP1 led to growth retardation and delayed ossification typified by enlarged hypertrophic zones in growth plates and disorganized chondro-osseous junctions. Furthermore, loss of ASAP1 led to delayed adipocyte development and reduced fat depot formation. Consistently, deletion of ASAP1 resulted in accelerated chondrogenic differentiation of mesenchymal cells in vitro, but suppressed osteo- and adipogenic differentiation. Mechanistically, we found that FAK/Src and PI3K/AKT signaling is compromised in Asap1(GT/GT) MEFs, leading to impaired adipogenic differentiation. Dysregulated FAK/Src and PI3K/AKT signaling is also associated with attenuated osteogenic differentiation. Together these observations suggest that ASAP1 plays a decisive role during the differentiation of mesenchymal progenitor cells. Author summary Mesenchymal progenitor cells are capable of differentiating into a number of lineages including osteoblasts, chondrocytes and adipocytes, and have therefore attracted interest for their potential application in regenerative medicine. Furthermore, defects in mesenchymal progenitor cell differentiation are considered to contribute to various diseases including metabolic syndrome, obesity and osteoporosis. In this study, we analyzed mice deficient in the multi-adaptor protein ASAP1, which has been implicated in tumor progression and metastasis. These mice display growth retardation, and a delayed development of bone and fat tissue. Consistently, mesenchymal progenitor cells deficient in ASAP1 exhibited enhanced differentiation into chondrocytes, but impaired differentiation into adipocytes and osteoblasts. Together these observations suggest that ASAP1 plays a decisive role during the differentiation of mesenchymal stem cells, which may be relevant for a number of diseases such as cancer.