Functions of gelsolin: Motility, signaling, apoptosis, cancer

Current Opinion in Cell Biology

Volumn 11, Issue 1, 1999, Pages 103-108

  Kwiatkowski, David J ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GELSOLIN; LYSOPHOSPHATIDIC ACID; PHOSPHATIDYLINOSITIDE;

APOPTOSIS; CANCER; CELL MOTILITY; PRIORITY JOURNAL; REVIEW; SKIN FIBROBLAST;

EID: 0032966363     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(99)80012-X     Document Type: Article

References (57)

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7. 2+ is not currently available. Residues that bind phosphoinositides are seen adjacent to those which bind to the side of an actin filament, explaining phosphoinositide-mediated uncapping and inhibition of severing.
8. McGough A, Chiu W, Way M Determination of the gelsolin binding site on F-actin: implications for severing and capping. Biophys J. 74:1998;764-772.
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14. Lueck A, Brown D, Kwiatkowski DJ The actin-binding proteins adseverin and gelsolin are both highly expressed but differentially localized in kidney and intestine. J Cell Sci. 111:1998;3633-3643. In the mouse and humans, adseverin is found to be most highly expressed in certain renal tubular and intestinal epithelial cells, with lower levels in the thymus, adrenal gland (but not medulla), and uterus, and very low to no expression elsewhere. In addition, expression of adseverin and gelsolin in the kidney are complementary, occurring for the most part in different tubular epithelial cell populations.
15. 2+ activated severing activity, but no nucleating activity.
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17. Liu YT, Yin HL Identification of the binding partners for flightless, I, a novel protein bridging the leucine-rich repeat and the gelsolin superfamilies. J Biol Chem. 273:1998;7920-7927. Human flightless I binds to actin-sepharose. The yeast two-hybrid method was used to identify flightless I LRR associated protein (FLAP), a binding partner of the flightless I LRR. FLAP is widely expressed and consists of 626 amino acids, but has unknown function.
18. Marks PW, Arai M, Bandura JL, Kwiatkowski DJ Advillin (p92): a new member of the gelsolin/villin family of actin regulatory proteins. J Cell Sci. 111:1998;2129-2136. A new member of the gelsolin family is described that is most closely homologous to villin. Advillin shares the six domain structure of other gelsolin family members and, in addition, has a carboxy-terminal headpiece domain that is similar to the headpiece domain of villin. Advillin is expressed at highest levels in developing and adult ganglia in the mouse, with much lower levels expressed in the uterus and intestine, and little to none elsewhere.
19. Wang XZK, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H, Ron D Identification of novel stress-induced genes downstream of chop. EMBO J. 17:1998;3619-3630.
20. Pestonjamasp KN, Pope RK, Wulfkuhle JD, Luna EJ Supervillin (p205): a novel membrane-associated, F-actin-binding protein in the villin/gelsolin superfamily. J Cell Biol. 139:1997;1255-1269. Supervillin is purified and cloned. It is a 205 kDa protein that purifies with neutrophil plasma membranes and binds to the sides of actin filaments in overlay assays. The protein is found in different intracellular locations in neutrophils, HeLa and MDCK cells, depending upon culture conditions and treatments. Structurally it consists of an amino-terminal half with apparent nuclear localization function, and a carboxy-terminal half with weak overall similarity to villin, and stronger similarity in regions of actin-binding activity.
21. Meerschaert K, De Corte V, De Ville Y, Vandekerckhove J, Gettemans J Gelsolin and functionally similar actin-binding proteins are regulated by lysophosphatidic acid. EMBO J. 17:1998;5923-5932. An extensive survey of phospholipids led to the discovery that gelsolin binds to lysophosphatidic acid (LPA). LPA binding affects gelsolin function in a manner similar to phosphoinositides, but requires significantly higher concentrations of LPA. LPA has synergistic effects on gelsolin function when added to phosphoinositides; therefore, LPA may act as another intracellular component that regulates gelsolin activity on the actin cytoskeleton. Secreted gelsolin may also serve as a carrier of LPA and perhaps other phospholipids, significantly affecting their presentation to and function on cells.
22. Suhler E, Lin W, Yin HL, Lee WM Decreased plasma gelsolin concentrations in acute liver failure, myocardial infarction, septic shock, and myonecrosis. Crit Care Med. 25:1997;594-598.
23. Maury CP, Sletten K, Totty N, Kangas H, Liljestrom M Identification of the circulating amyloid precursor and other gelsolin metabolites in patients with G654A mutation in the gelsolin gene (Finnish familial amyloidosis): pathogenetic and diagnostic implications. Lab Invest. 77:1997;299-304.
24. Paunio T, Kangas H, Heinonen O, Buc-Caron MH, Robert JJ, Kaasinen S, Julkunen I, Mallet J, Peltonen L Cells of the neuronal lineage play a major role in the generation of amyloid precursor fragments in gelsolin-related amyloidosis. J Biol Chem. 273:1998;16319-16324. The authors disrupt the Cys188-Cys201 disulfide bond in gelsolin by site-directed mutagenesis and find that aberrant intracellular processing occurs, similar to that seen in Asp187→Asn amyloidogenic gelsolin. The implication is that the Asp187→Asn mutation disrupts this disulfide bond, leading to cleavage. In addition, this intracellular cleavage occurs at a higher rate in neuronal lineage cells than in other cell types.
25. Witke W, Sharpe AH, Hartwig JH, Azuma T, Stossel TP, Kwiatkowski DJ Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin. Cell. 81:1995;41-51.
26. Azuma T, Witke W, Stossel TP, Hartwig JH, Kwiatkowski DJ Gelsolin is a downstream effector of Rac for fibroblast motility. EMBO J. 17:1998;1362-1370. Gelsolin-null dermal fibroblasts are characterized in detail in comparison to wild-type fibroblasts. The gelsolin-null cells have increased F-actin, and reduced motility and pinocytosis in several assay systems. They crawl using a distinctive filopodia-like structure in contrast to the ruffles and lamellipodia present in the wild-type cells. Both the gelsolin-null cells and tissues from the gelsolin-null mice show expression of Rac at fivefold higher levels than wild-type cells, and the motility defect and Rac overexpression are reverted to wild-type by transfection of gelsolin. The implication is that gelsolin is an obligate element downstream of the Rac GTPase for motility.
27. 2+ influx in response to glutamate compared to wild-type neurons. Enhanced currents in response to NMDA were also seen in patch-clamp experiments, as a result of a lack of current rundown. Cultured neurons showed greater cell death in response to high-dose glutamate, and seizure-induced damage to hippocampal pyramidal neurons was increased in adult gelsolin-null mice. The implication is that gelsolin has an important role in modulating neuronal ion channel function in response to excitotoxicity in vivo.
28. Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science. 278:1997;294-298. Screening of 100,000 murine embryo fibroblast cDNA clones in an in vitro transcription-translation reaction led to identification of gelsolin as the most prominent substrate of caspase-3. The amino-terminal gelsolin fragment generated by caspase-3 cleavage has unregulated actin filament severing activity, and when expressed in cells causes apoptosis. Gelsolin-null neutrophils have a slower rate of apoptotic death in response to tumor necrosis factor induction, compared to wild-type neutrophils. The implication is that gelsolin has an important role in apoptotic progression.
29. Lu M, Witke W, Kwiatkowski DJ, Kosik KS Delayed retraction of filopodia in gelsolin null mice. J Cell Biol. 138:1997;1279-1287. Although growth cone extension, ruffling activity, and translocational rates are identical in cultured gelsolin null neurons compared to wild-type, the null neurons have increased numbers of neurite filopodia. This is due to delayed filopodial retraction that implicates a function of gelsolin in dissassembling the F-actin rich core of the filopodia.
30. Rosenblatt J, Agnew BJ, Abe H, Bamburg JR, Mitchison TJ Xenopus actin depolymerizing factor/cofilin (XAC) is responsible for the turnover of actin filaments in Listeria monocytogenes tails [see comments]. J Cell Biol. 136:1997;1323-1332.
31. Laine RO, Phaneuf KL, Cunningham CC, Kwiatkowski D, Azuma T, Southwick FS Gelsolin, a protein that caps the barbed ends and severs actin filaments, enhances the actin-based motility of Listeria monocytogenes in host cells. Infect Immun. 66:1998;3775-3782. Listeria motility and actin tail lengths were both significantly increased in NIH3T3 cells that had been transfected to overexpress gelsolin, and the increases were proportional to the level of gelsolin expression.
32. Arora PD, McCulloch CAG Dependence of fibroblast migration on actin severing activity of gelsolin. J Biol Chem. 271:1996;20516-20523.
33. Chen P, Murphy-Ullrich JE, Wells A A role for gelsolin in actuating epidermal growth factor receptor-mediated cell motility. J Cell Biol. 134:1996;689-698.
34. Arcaro A The small GTP-binding protein Rac promotes the dissociation of gelsolin from actin filaments in neutrophils. J Biol Chem. 273:1998;805-813. Gelsolin-actin complexes are present in resting neutrophils and are dissociated by fMLP (f-Met-Leu-Phe, a chemotactic peptide for neutrophils) activation. Here this effect is shown to be insensitive to wortmannin or kinase inhibitor treatment. In a cell-free system, gelsolin-actin dissociation was achieved by addition of GTP-loaded Rac or heterotrimeric G proteins, implicating a signaling pathway between Rac and gelsolin that is independent of phosphoinositides.
35. Barkalow K, Witke W, Kwiatkowski DJ, Hartwig JH Coordinated regulation of platelet actin filament barbed ends by gelsolin and capping protein. J Cell Biol. 134:1996;389-399.
36. Wang JS, Coburn JP, Tauber AI, Zaner KS Role of gelsolin in actin depolymerization of adherent human neutrophils. Mol Biol Cell. 8:1997;121-128.
37. Cantiello H Role of actin filament organization in cell volume and ion channel regulation. J Exp Zool. 279:1997;425-435.
38. Lascola CD, Nelson DJ, Kraig RP Cytoskeletal actin gates a Cl-channel in neocortical astrocytes. J Neurosci. 18:1998;1679-1692.
39. 2+ required for this effect. The implication is that during cell activation, the affinity of gelsolin and capG for phosphoinositides is increased, potentially altering phosphoinositides signaling pathways.
40. Flanagan LA, Cunningham CC, Chen J, Prestwich GD, Kosik KS, Janmey PA The structure of divalent cation-induced aggregates of PIP2 and their alteration by gelsolin and tau. Biophys J. 73:1997;1440-1447. Divalent cations cause phosphatidylinositol 4,5-bisphosphate to aggregate into clusters of striated filaments. Gelsolin and tau, but not profilin, affected the structure of these aggregates, confirming gelsolin's high affinity binding and suggesting it can alter phosphatidylinositol 4,5-bisphosphate distribution in the cell membrane.
41. Sun H, Lin K, Yin HL Gelsolin modulates phospholipase C activity in vivo through phospholipid binding. J Cell Biol. 138:1997;811-820. Utilizing NIH3T3 cells stably transfected to overexpress gelsolin or capG, it is shown that overexpression of either protein strongly inhibits bradykinin-stimulated phospholipase Cβ and weakly inhibits tyrosine kinase-stimulated phospholipase Cγ. Specificity of the gelsolin effect on phospholipase Cβ was confirmed in washout and addback experiments performed on permeabilized cells. The implication is that these proteins can significantly affect phosphoinositide-signaling pathways in cells.
42. Banno Y, Nakashima T, Kumada T, Ebisawa K, Nonomura Y, Nozawa Y Effects of gelsolin on human platelet cytosolic phosphoinositide-phospholipase C isozymes. J Biol Chem. 267:1992;6488-6494.
43. Steed PM, Nagar S, Wennogle LP Phospholipase D regulation by a physical interaction with the actin-binding protein gelsolin. Biochemistry. 35:1996;5229-5237.
44. Singh SS, Chauhan A, Murakami N, Chauhan VP Profilin and gelsolin stimulate phosphatidylinositol 3-kinase activity. Biochemistry. 35:1996;16544-16549.
45. Baldassare JJ, Henderson PA, Tarver A, Fisher GJ Thrombin activation of human platelets dissociates a complex containing gelsolin and actin from phosphatidylinositide-specific phospholipase Cγ1. Biochem J. 324:1997;283-287. Co-immunoprecipitation experiments demonstrate that phospholipase Cγ is associated with a gelsolin-actin complex in fresh unstimulated platelets, and that this three-protein complex dissolves in response to thrombin stimulation, requiring platelet aggregation and tyrosine phosphorylation events. Phospholipase Cγ activity increases concurrent with release from gelsolin.
46. Chellaiah M, Fitzgerald C, Alvarez U, Hruska K c-Src is required for stimulation of gelsolin-associated phosphatidylinositol 3-kinase. J Biol Chem. 273:1998;11908-11916. Osteopontin stimulation of osteoclasts induces binding of c-Src to gelsolin in co-immunoprecipitation assays, in addition to phosphatidylinositol 3-kinase (as shown previously by these authors). Treatment of osteoclasts with antisense oligonucleotides against c-Src led to reduced c-Src expression, reduced association between gelsolin and c-Src in osteoclast extracts, reduced associated phosphatidylinositol 3-kinase activity and reduced bone resorption.
47. De Corte V, Gettemans J, Vandekerckhove J Phosphatidylinositol 4,5-bisphosphate specifically stimulates PP60(c-src) catalyzed phosphorylation of gelsolin and related actin-binding proteins. FEBS Lett. 401:1997;191-196.
48. Cryns V, Yuan J Proteases to die for. Genes Dev. 12:1998;1551-1570.
49. Kamada S, Kusano H, Fujita H, Ohtsu M, Koya RC, Kuzumaki N, Tsujimoto Y A cloning method for caspase substrates that uses the yeast two-hybrid system: cloning of the antiapoptotic gene gelsolin. Proc Natl Acad Sci USA. 95:1998;8532-8537. A mutant caspase-3 was used in the yeast two-hybrid system to identify binding partners of caspase-3. Gelsolin was identified as a prominent substrate, and its cleavage confirmed in vitro.
50. Geng Y-JAT, Tang JX, Hartwig JH, Muszynski M, Libby P, Kwiatkowski DJ Caspase-3 induced gelsolin fragmentation contributes to actin cytoskeletal collapse, nucleolysis, and apoptosis of vascular smooth muscle cells exposed to proinflammatory cytokines. Eur J Cell Biol. 50:1999;294-302.
51. Ohtsu M, Sakai N, Fujita H, Kashiwagi M, Gasa S, Shimizu S, Eguchi Y, Tsujimoto Y, Sakiyama Y, Kobayashi K, Kuzumaki N Inhibition of apoptosis by the actin-regulatory protein gelsolin. EMBO J. 16:1997;4650-4656. Stable gelsolin-overexpressing transfectant lines were derived from the Jurkat cell line, a human T-cell line. These cell lines were found to have marked resistance to apoptotic induction to anti-fas antibodies, C2-ceramide, and dexamethasone, and a marked reduction in the production of caspase-3 activity. The implication is that gelsolin is blocking apoptosis at some critical and universal early step in these cells.
52. Asch HL, Head K, Dong Y, Natoli F, Winston JS, Connolly JL, Asch BB Widespread loss of gelsolin in breast cancers of humans, mice, and rats. Cancer Res. 56:1996;4841-4845.
53. Prasad SC, Thraves PJ, Dritschilo A, Kuettel MR Protein expression changes associated with radiation-induced neoplastic progression of human prostate epithelial cells. Electrophoresis. 18:1997;629-637.
54. Dosaka-Akita H, Hommura F, Fujita H, Kinoshita I, Nishi M, Morikawa T, Katoh H, Kawakami Y, Kuzumaki N Frequent loss of gelsolin expression in non-small cell lung cancers of heavy smokers. Cancer Res. 58:1998;322-327. Gelsolin expression was reduced in twelve out of twelve human lung cancer cell lines - markedly so (<10% normal levels) in ten of the twelve. Of 88 primary resected tumors 48 (55%) had no gelsolin expression, and there was no correlation with histologic type or stage.
55. Kwon HJ, Yoshida M, Nagaoka R, Obinata T, Beppu T, Horinouchi S Suppression of morphological transformation by radicicol is accompanied by enhanced gelsolin expression. Oncogene. 15:1997;2625-2631. Radicicol, an inhibitor of src-family kinases, reverts the morphology of transformed fibroblasts to untransformed fibroblasts. In two-dimensional gel analyses, gelsolin was identified as being prominently upregulated in radicicol-treated cells, similar to what the authors have seen previously with trichostatin A treatment. Injection of anti-gelsolin antibodies inhibited the morphologic reversion induced by radicicol in T24 and HeLa cells.
56. Shieh DGJ, Sugarbaker DJ, Herndon J, Kwiatkowski DJ Motility as a prognostic factor in non-small cell lung cancer: role of gelsolin expression. Cancer. 85:1999;47-57. Analysis of histologic sections from 229 patients with stage I non-small cell lung cancer was performed. Rac and ABP-280 expression (an actin filament crosslinking protein, also known as filamin) appeared to have no influence on prognosis in a pilot study, but gelsolin expression was important. The 32 patients who expressed gelsolin highly (either uniformly or focally in their tumors) had a fourfold higher relative risk of cancer recurrence, and gelsolin expression was a greater risk factor than any other variable examined.
57. 2+ levels after glucose/oxygen deprivation. In addition, infarct volumes are 36% greater in gelsolin-null mice than wild-type controls after transient middle cerebral artery occlusion. This increased stroke volume is eliminated by intraventricular injection of cytochalasin D, which also decreases stroke volume in wild-type mice. The implication is that modulation of the actin filament architecture by gelsolin and analogues such as cytochalasin D may improve the outcome from stroke.