Tumor metastasis requires cell motility driven by actin cytoskeleton dynamics, cell adhesion turnover and actomyosin contractility. Regulation of the actin cytoskeleton plays a pivotal role in protrusion formation, membrane internalization, force generation and intracellular trafficking. Many proteins which affect actin dynamics are found to be involved in tumorigenesis and metastasis. Among them, formin proteins as the largest group of actin nucleators are emerging to be candidates of drug targets for cancer therapy. However, the knowledge of formins in cancer cell invasion is limited. One member of the formin family, FMNL2 (formin-like 2), is mutated or upregulated in various cancer types. In this work, FMNL2 is shown to be phosphorylated by PKCα at the residue Ser 1072. Phosphorylation of FMNL2 partially releases autoinhibition leading to higher activity. FMNL2-driven cancer cell invasion into 3D matrix is further enhanced by phosphorylation of the Ser 1072 residue. In addition, phosphorylation of FMNL2 by PKCα results in the internalization of FMNL2 from the plasma membrane through endocytic routes. Internalization of FMNL2 is reversible. Mutation of Ser 1072 into Ala impedes the rate of internalization. Internalized FMNL2 appears to colocalize with the α5 integrin positive vesicles, which is consistent with the fact that FMNL2 interacts with the cytoplasmic tail of α5 integrin. Furthermore, FMNL2 is required for β1 integrin internalization. Together with the fact that actomyosin contractility is reduced when FMNL2 is silenced, it is proposed here that FMNL2 drives cancer cell invasion through the regulation of integrin trafficking and actomyosin contractility.
|Supervisor:||Steinbeisser, Prof. Dr. Herbert|
|Date of thesis defense:||10 October 2013|
|Date Deposited:||14 Nov 2013 12:40|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Subjects:||570 Life sciences|