Abstract
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 Asap1GT/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.
Highlights
Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of differentiating into a number of lineages including osteoblasts, chondrocytes and adipocytes
Mesenchymal progenitor cells are capable of differentiating into a number of lineages including osteoblasts, chondrocytes and adipocytes, and have attracted interest for their potential application in regenerative medicine
As ASAP1 interacts with focal adhesion kinase (FAK) and Src via its proline-rich and SH3 domains [23, 26], and both molecules are functionally involved in adipogenic differentiation [14, 15], we hypothesized that dysregulated FAK/Src signaling may contribute to the phenotype observed in Asap1GT/GT MEFs. Consistent with this notion, we found that phosphorylation of FAK was reduced in ASAP1-deficient MEFs after induction of adipogenic differentiation compared to wild-type controls (Fig 8A)
Summary
Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of differentiating into a number of lineages including osteoblasts, chondrocytes and adipocytes. Due to their multipotency, MSCs have attracted interest for their potential application in regenerative medicine. Mesenchymal differentiation is regulated by key transcription factors that are specific for each lineage. Osteogenic differentiation is driven by the transcription factor Runx, and leads to the formation of new bone in the process of osteogenesis. Together with the osteoblast-specific transcription factor osterix, Runx induces the expression of matrix proteins such as osteocalcin, osteopontin, bone sialoprotein and collagen I, which leads to the maturation of osteoblasts and subsequent mineralization of the bone matrix [4, 5]
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