calcitonin gene related peptide In summary we suggest that b

In summary, we suggest that both cofilin and gelsolin are essential factors that regulate sperm capacitation and the acrosomal exocytosis by modulating actin. The relationships between activation/inactivation of cofilin and gelsolin suggest that inhibition of cofilin is important for allowing F-actin formation at the beginning of the capacitation process, whereas inhibition of gelsolin is important later on during the capacitation process. Moreover, the different regulation of the actin-severing proteins, in which gelsolin activity is regulated by PIP2 and PLC whereas cofilin is not, and the fact that gelsolin activation but not cofilin is calcium-regulated [78], suggest a better and safer way to control actin dynamics during sperm capacitation. The need for two actin-severing proteins, or perhaps more, and at least two pathways, PLD and CaMKII for regulation actin remodeling emphasize the importance of this process for achieving successful fertilization.
Conflicts of interest
Introduction Pre-mRNA processing factor 4B (PRP4), first identified in Schizosaccharomyces pombe, is a protein involved in pre-mRNA splicing [1]. Human PRP4 encodes a 1007-amino calcitonin gene related peptide protein which contains an N-terminal 340-amino acid arginine/serine-rich domain, that is commonly found in pre-mRNA splicing factors [2]. PRP4 has been found to be an essential kinase for pancreatic cancer cell survival, as well as its kinase activity has been determined to induce drug resistance in ovarian cancer [3], [4]. Previously we reported that PRP4 was involved in modulating actin cytoskeleton [5]. The actin cytoskeleton contributes to a wide variety of cellular and developmental processes such as mechanical support, cell migration, cell adhesion, cell-cell interaction, and signal transduction [6], [7], [8]. Extracellular stimuli generate changes in the actin cytoskeleton at specific sites, primarily through Rho proteins. Rho proteins cycle between an active guanosine-5′-triphosphate (GTP)-bound state and an inactive guanosine-5′-diphosphate (GDP)-bound state. Their activation state is controlled by regulatory proteins such as guanine exchange factors (GEFs), guanine dissociation inhibitors (GDIs), and GTPase activating proteins (GAPs) [9]. To date, approximately 20 Rho GTPases have been reported in humans, of which Rho, Rac, and Cdc42 are the best studied [10]. Upon activation, Rho GTPases directly or indirectly affect the local assembly or disassembly of F-actin [11]. Several proteins, including Rho-associated protein kinase (ROCK), formins, and other scaffolding molecules, have been identified as downstream targets of RhoA [12]. ROCK, the major target of RhoA, directly phosphorylates Lim kinase (LIMK), an actin cytoskeleton regulator [13], [14]. Activation of LIMK by ROCK leads to direct phosphorylation of cofilin at Ser3 [15]. Cofilin belongs to the actin depolymerizing factor (ADF)/cofilin protein family, consisting of ADF, cofilin 1, and cofilin 2. Cofilin 1 (hereafter referred to as cofilin) is the most abundant and ubiquitous member of the ADF/cofilin protein family in vertebrate non-muscle tissues, and is the only member required for viability [16]. Cofilin is a key regulator of actin severing, nucleation, and capping within the protrusive machinery [15], [16], [17], [18]. The phosphorylation of cofilin at Ser3 blocks the actin binding interface, preventing its actin binding function (inactive cofilin form), and promotes F-actin stability and elongation, whereas dephosphorylation restores cofilin actin-related activity [16], [19]. Phosphatases are enzymes that dephosphorylate proteins, effectively reversing the action of kinases. To date, approximately 226 known phosphatases have been reported, which have been classified into 3 families: phosphoprotein phosphatase (PPP) family, metallo-dependent protein phosphatase (PPM) family, and protein-tyrosine phosphatase (PTP) family [20], [21]. The PPP family includes PP1, PP2A, PP2B, and PP4–7, which are responsible for most dephosphorylation reactions of phosphoserine and phosphotreonine (pSer/pThr), and some phosphotyrosine (pTyr) [22], [23]. Phosphorylation can either activate or inactivate a protein [24]. As described earlier, phosphorylation of cofilin by LIMK at Ser3 suppresses its function, whereas dephosphorylation restores the actin-related activity. A study reported that formate dehydrogenase (FDH; a folate enzyme with tumor suppressor-like properties) induced dephosphorylation of cofilin by PP1 and PP2A in A549 cells, which resulted in F-actin stabilization, re-distribution of cytoplasmic actin, formation of actin stress fibers, and inhibition of cell motility [25]. Several studies have reported on specific, unconventional cofilin phosphatases that reactivate cofilin regulatory functions [26]. An investigation reported that chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily, directly dephosphorylates cofilin with high specificity and co-localizes with cofilin in motile and dividing cells. The loss of CIN activity repressed cofilin activity, which resulted in F-actin stabilization and massive cell division defects [27]. Slingshot family of phosphatases (SSH1, 2, and 3) has been also reported to be cofilin-specific phosphatases, which facilitates the activation of cofilin by dephosphorylation, restoring its actin depolymerizing activity and induces cell motility [28], [29], [30].