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    • br There is evidence to suggest that GMF activities are

    2022-11-07


    There is evidence to suggest that GMF activities are regulated in vivo by post-translational modification. indeed, there is strong precedent for ADF-homology family proteins being regulated in this manner. Cofilin is inhibited by phosphorylation of a serine residue at its N terminus. This residue lies within the G/F-actin binding site of cofilin, and its phosphorylation by LIM kinase weakens F-actin binding and increases cofilin’s cooperativity of binding, leading to reduced mechanical discontinuities and reduced severing 61, 62. Phosphorylation of GMFγ at its analogous Ser2 also has a regulatory role. Purified phosphomimetic GMFγ (S2E) has weakened affinity for the Arp2/3 complex [54], and phosphorylated GMFγ in vivo accumulates more strongly on Anhydrotetracycline hydrochloride networks at the leading edge, possibly the result of failed network debranching [11]. Furthermore, signaling from GTPases Rac1 and Cdc42 promotes the phosphorylation of GMFγ at Ser2, as well as increased accumulation of GMFγ and F-actin at the leading edge and increased lamellipodial protrusion. Thus, it is possible that Ser2 phosphorylation of GMF inactivates its debranching activity to disrupt lamellipodial retraction and promote protrusion [10]. Although the kinase that phosphorylates Ser2 on GMF has not yet been identified, LIM kinase is an intriguing candidate, as this would provide a mechanism for coordinately regulating cofilin and GMF. There are a number of additional putative phosphorylation sites on GMF (Figure 3). In GMFβ, four different Ser or Thr residues are predicted to be phosphorylated by one or more of the following kinases: PKA, PKC, CKII, and S6K [63]. These residues are conserved in GMFγ, which has two additional PKC and CKII kinase consensus sites not found in GMFβ [5]. Some of these phosphorylation sites have been implicated in the suggested role of GMF in MAP kinase signaling [64], as discussed below. Interestingly, all four sites shared by GMFβ and GMFγ reside in or near functional ‘Site 2’ (Figure 3) [26], where GMF contacts the first actin subunit in the daughter filament, and therefore could regulate debranching. Additionally, phosphorylation on Tyr104 by c-abl kinase weakens GMFγ interactions with the Arp2/3 complex in smooth muscle cells and alters F-actin levels [65]. Tyr104 is located near GMFγ ‘Site 1’ (Figure 3), which contacts the Arp2/3 complex, consistent with its effects on GMFγ–Arp2/3 interactions. However, the side chain of Tyr104 is not surface-exposed on available structures of GMF, so it is not yet clear how c-abl gains access to this site. Continued investigation into how phosphorylation at each of these sites influences GMF activities and cellular functions is likely to reveal new mechanisms by which cells spatially and temporally tune actin network remodeling and turnover.
    Reconciling the Actin Functions of GMF with Its Roles in Signaling and Disease GMF was initially identified as a factor present in brain extracts that induces differentiation of glioblast, glioma, and neuroblastoma cells in culture 1, 2, 3, 4. Subsequent studies indicated that GMFβ elicits these effects via: (i) an extracellular route, without being internalized by the recipient cells, suggesting GMFβ is a secreted protein [66]; and/or (ii) an intracellular signaling pathway [67]. Since GMFβ lacks a clear signal sequence for classical targeting to the secretory pathway, its release from cells could occur through nonclassical ‘leaderless’ secretion68, 69. In astrocytes, GMFβ is detected both in the cytosol and on the cell surface [67]. However, GMFβ activity has not been detected in astrocyte-conditioned media [70], suggesting healthy cells may not secrete GMFβ. GMFβ also has been identified as a surface-expressed protein on thymic epithelial cells that mature into CD4+ (helper) T cells [71]; however, this may be due to autoimmune regulator (AIRE)-induced expression of non-thymic proteins used to educate developing T cells and prevent autoimmunity [72]. Thus, while it is intriguing to consider roles for GMF in functioning outside of the cell, this model requires further investigation. One possibility that warrants exploration is that GMFβ might be released specifically from sick or dying cells.