Disease relevance of Gsn

• We have shown that osteopontin (OP) binding to the alpha(v)beta(3) integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, pp(60c-src), and phosphatidylinositol 3'-kinase [1].
• The Ca2+-sensitive actin-severing protein gelsolin concentrates in the Listeria rocket tails at normal resting [Ca2+]i and disassociates from the tails when [Ca2+]i is lowered [2].
• We expressed both proteins in Escherichia coli and show that mouse adseverin displays the typical characteristics of all members of the gelsolin family with respect to actin binding (capping, severing, and nucleation) and its regulation by Ca2+ [3].
• Southern analysis revealed no major mutations in the gelsolin gene of human breast cancer cells [4].
• Gelsolin was also missing or greatly decreased in 70% of 30 human sporadic, invasive breast carcinomas examined by immunocytochemistry and in 100% of virally induced mouse and chemically induced rat mammary carcinomas evaluated by Northern analysis [4].

Psychiatry related information on Gsn

• To understand the distinct functions of the closely related actin-severing proteins adseverin and gelsolin, we examined the expression of these proteins in detail during mouse and human development using a new highly sensitive and specific set of antibody reagents [5].

High impact information on Gsn

• The knockdown phenotype was rescued by a CP mutant refractory to shRNA, but not by another barbed-end capper, gelsolin, demonstrating that the phenotype was specific for CP [6].
• Gelsolin, an 82 kDa actin-binding protein, has potent actin filament-severing activity in vitro [7].
• To investigate the in vivo function of gelsolin, transgenic gelsolin-null (Gsn-) mice were generated and found to have normal embryonic development and longevity [7].
• However, platelet shape changes are decreased in Gsn- mice, causing prolonged bleeding times [7].
• Neither gelsolin nor other proteins with similar actin filament-severing activity are expressed in early embryonic cells, indicating that this mechanism of actin filament dynamics is not essential for motility during early embryogenesis [7].

Chemical compound and disease context of Gsn

• We sought to assess the effects of gelsolin overexpression on metastasis and to determine the importance of a carboxyl-terminus that confers Ca(2+) dependency on gelsolin for effects of its overexpression [8].
• Vulnerability of cultured hippocampal neurons to glutamate toxicity was greater in cells lacking gelsolin [9].
• Because both gelsolin deficiency and PI3K inhibition impair bone resorption, we conclude that phosphatidylinositol 3,4,5-trisphosphate-based protein interactions are critical for osteoclast function [10].
• Gelsolin, with its asparagine 187 mutation, was found to cause amyloidosis beyond the borders of Finland, where it has been extensively evaluated [11].

Biological context of Gsn

• Here we demonstrate that female mice with a targeted deletion of the gelsolin gene (Gsn-/-) have defects in mammary gland morphogenesis [12].
• These observations establish the requirement of gelsolin for rapid motile responses in cell types involved in stress responses such as hemostasis, inflammation, and wound healing [7].
• Lactation and involution in the gelsolin-null animals were similar to those of wild-type mice [12].
• Gelsolin is an actin-binding protein that regulates actin filament-severing and capping activity in the various processes of cell motilities [13].
• To test this hypothesis, we have analyzed the kinetics of severing by gelsolin, adseverin, and a gelsolin truncate which lacks the C-terminal latch [14].

Anatomical context of Gsn

• Transplantation of GsnWT epithelium into the Gsn-/- fat pad recapitulated the lack of terminal branching seen in Gsn-/- females [12].
• Lobuloalveolar development was delayed in response to pregnancy in mammary glands of Gsn-/- mice but was otherwise normal [12].
• Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin [7].
• Gelsolin was expressed in the distal convoluted tubule, intercalated cells and principal cells of cortical and medullary collecting ducts, and in ureter [5].
• Here, we report the expression of gelsolin mRNA and protein in the hippocampus following transections of the entorhinal afferents [13].

Associations of Gsn with chemical compounds

• It has been shown that actin polymerization is controlled by gelsolin, whose interactions with actin are activated by calcium ion (Ca2+) and inhibited by membrane polyphosphoinositides (PPI) [15].
• We show that gelsolin-null neurons have enhanced cell death and rapid, sustained elevation of Ca2+ levels following glucose/oxygen deprivation, as well as augmented cytosolic Ca2+ levels in nerve terminals following depolarization in vitro [16].
• Gelsolin and functionally similar actin-binding proteins are regulated by lysophosphatidic acid [17].
• These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the alpha(v)beta(3) integrin [1].
• We determined here whether phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] regulation of gelsolin is required for collagen internalization [18].

Physical interactions of Gsn

• Gelsolin in complex with phosphatidylinositol 4,5-bisphosphate inhibits caspase-3 and -9 to retard apoptotic progression [19].
• Previously, we have reported that osteopontin (OPN) binding to integrin alphavbeta3 increased the levels of gelsolin-associated polyphosphoinositides, podosome assembly/disassembly, and actin filament formation [20].

Enzymatic interactions of Gsn

• Caspase-cleaved gelsolin severed actin filaments in vitro in a Ca2+-independent manner [21].
• Caspase-3 activation was also significantly enhanced in KO mice versus WT mice, as evidenced by higher levels of activated caspase-3 and cleaved gelsolin [22].
• Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice [23].

Regulatory relationships of Gsn

• Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background [24].
• Caspase-3-induced gelsolin fragmentation contributes to actin cytoskeletal collapse, nucleolysis, and apoptosis of vascular smooth muscle cells exposed to proinflammatory cytokines [25].
• The cytoplasmic protein tyrosine phosphatase (PTP)-proline-glutamic acid-serine-threonine amino acid sequences (PEST) was also found to be associated with gelsolin in osteoclast podosomes and with stimulation of alpha(v)beta(3)-regulated phosphorylation of PTP-PEST [10].

Other interactions of Gsn

• Mbh1 encodes a polypeptide structurally similar to the actin-severing proteins gelsolin and severin [26].
• Calcium regulation of gelsolin and adseverin: a natural test of the helix latch hypothesis [14].
• The loci for gelsolin and dopamine beta-hydroxylase therefore form part of the conserved synteny between HSA9q and MMU2 [27].
• Moreover, selective expression of gelsolin in sinusoidal endothelial cells indicates a pivotal role for interactions between sinusoidal endothelial cells and liver parenchymal cells in Fas ligand-mediated liver failure [28].
• The proapoptotic genes induced only in LTR6 cells like Apaf-1, Sumo-1 and gelsolin among others may suggest a possible explanation for apoptosis in LTR6 cells [29].

Analytical, diagnostic and therapeutic context of Gsn

• Immunohistochemistry on murine kidney sections revealed a predominantly differential localization of adseverin and gelsolin [5].
• Northern blot analysis showed that transcript of gelsolin was upregulated in a transient manner in the deafferented hippocampus by 1.3-, 2.1-, 1.7-, and 1.1- folds of controls, respectively, at 1, 3, 7, and 15 days postlesion (dpl) [13].
• By in situ hybridization to murine embryo sections, we show that gelsolin expression is widespread but focal from e12.5 onward, with the exception of brain and mucosal epithelium [30].
• Molecular cloning of human macrophage capping protein cDNA. A unique member of the gelsolin/villin family expressed primarily in macrophages [31].
• Sequence analysis and chromosomal localization of human Cap Z. Conserved residues within the actin-binding domain may link Cap Z to gelsolin/severin and profilin protein families [32].

References