Complex roles of filamin-A mediated cytoskeleton network in cancer progression

Abstract

Filamin-A (FLNA), also called actin-binding protein 280 (ABP-280), was originally identified as a non-muscle actin binding protein, which organizes filamentous actin into orthogonal networks and stress fibers. Filamin-A also anchors various transmembrane proteins to the actin cytoskeleton and provides a scaffold for a wide range of cytoplasmic and nuclear signaling proteins. Intriguingly, several studies have revealed that filamin-A associates with multiple non-cytoskeletal proteins of diverse function and is involved in several unrelated pathways. Mutations and aberrant expression of filamin-A have been reported in human genetic diseases and several types of cancer. In this review, we discuss the implications of filamin-A in cancer progression, including metastasis and DNA damage response.

Filamin A interacts with the coactivator MKL1 to promote the activity of the transcription factor SRF and cell migration

“…Metastasis, or leaving the primary tumor for invasion into other tissue parts, requires a strict cascade of locomotion events, including tumor cell detachment from the primary site, followed by tumor cell invasion, migration and colonization at the secondary sites (Arwert EN., Hoste E. et al, 2012). Metastasis requires the cancer cells to be able to adept to different cell shapes, resist to mechanical stress and to be highly motile (Yue J., Huhn S. et al, 2013). A great amount of these key processes are driven by FLNA as described in 2.4.3.…”

“…A great amount of these key processes are driven by FLNA as described in 2.4.3. Thus, it is conceivable that lack of FLNA would decrease the tumor cells ability regarding mobility and invasiveness and furthermore cause them to be more sensitive to mechanical stress (Yue J., Huhn S. et al, 2013). This demonstrates the irreparable role of FLNA in tumorigenesis and its medical relevance during the process of developing malfunctions.…”

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…Notably, lamins are known to regulate genomic stability as well as DNA damage repair (Gonzalo, 2014) and have been shown to interact with nuclear actin (Ho et al, 2013;Plessner et al, 2015;Simon et al, 2010). Multiple studies have identified other actin regulatory proteins that are able to translocate into the nucleus and are involved in the DNA response including JMY (Lin et al, 2014;Zuchero et al, 2009), filamin A (Yue et al, 2013), Arp5 (Kitayama et al, 2009), APC (Kouzmenko et al, 2008;Meniel et al, 2015;Narayan and Sharma, 2015), formin-2, spire-1/2 (Belin et al, 2015), myosin VI (Jung et al, 2006) and nuclear histone deacetylases (HDACs; Serebryannyy et al, 2016a), as well as p53, which is speculated to directly bind F-actin (Metcalfe et al, 1999). Furthermore, elegant in vitro studies have demonstrated that α-catenin forms a catch bond with F-actin when bound to β-catenin (Buckley et al, 2014).…”

Functions of nuclear actin-binding proteins in human cancer (Review)

“…The nuclear FLNα is associated with DNA damage repair (59). By contacting BRCA1 and breast cancer type 2 (BRCA2), nuclear FLNα is involved in the process of homologous recombinational and non-homologous DNA repair (60). Furthermore, FLNα interacts with BRCA1 with its extreme C-terminus and mediates BRCA1 and Rad51 foci formation following DNA damage (Fig.…”

“…1). The deficiency in FLNα makes the cells susceptible to ionizing radiation and delays the recovery from G2/M arrest, which may trigger the incidence of cancer (60)(61)(62)(63). Measurement of FLNα expression reveals that FLNα is negative in several melanomas (63).…”