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International Journal of Hematology 05/2012; 74(4):473-474. · 1.27 Impact Factor
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Heiwa Kanamori,
Yumiko Takaishi,
Maki Takabayashi,
Masatsugu Tanaka, Satoshi Yamaji,
Naoto Tomita,
Katsumichi Fujimaki,
Shin Fujisawa,
Shinichiro Watanabe,
Michio Matsuzaki,
Yoshiaki Tshigatsubo
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ABSTRACT: To clarify the clinical significance of the presence of fragmented red cells (FRC) after allogeneic bone marrow transplantation
(BMT), we measured the incidence and degree of FRC and their relationships to clinical features. The percentages of FRC (%FRC)
were measured in 50 patients on weeks-2,0,2,4,6,8,10, and 12. The %FRC in pre-BMT patients (mean, 0.52%; range, 0.04%–1.56%)
was higher than in healthy control subjects (mean, 0.08%; range, 0.02%–0.27%). The highest %FRC (≥1.3%) were seen in 2 pre-BMT
and 17 post-BMT patients. Right patients who developed thrombotic microangiopathy (TMA) showed %FRC values that were significantly
higher than those in patients without TMA. However, the timing of elevated %FRC was delayed until several days after the onset
of intravascular hemolysis and/or a drop in platelet count. Of the patients who did not experience TMA, 5 patients with infection
and 4 patients with acute graft-versus-host disease (GVHD) also showed significant elevation of %FRC during the clinical course.
Furthermore, multivariate analysis results demonstrated that TMA and infection had a statistically significant effect on the
high value of %FRC. These findings indicate that the appearance of FRC is a common phenomenon in patients undergoing BMT and
is not a predictive factor for the early diagnosis of TMA, although FRC is one of the main laboratory findings in TMA. Furthermore,
an increased %FRC is seen in other post-BMT clinical settings, such as infection and acute GVHD.
International Journal of Hematology 04/2012; 77(2):180-184. · 1.27 Impact Factor
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Takuya Miyazaki,
Yohei Kirino,
Mitsuhiro Takeno,
Sei Samukawa,
Maasa Hama,
Masatsugu Tanaka, Satoshi Yamaji,
Atsuhisa Ueda,
Naoto Tomita,
Hiroyuki Fujita,
Yoshiaki Ishigatsubo
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ABSTRACT: Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO-1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid-derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO-1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO-1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or -interferon, they significantly expressed both HO-1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO-1 expression in U937 cells but suppressed it in primary monocytes and PMA-treated U937 cells. In HO-1-expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf-recognition elements, the enhancer regions of the HO-1 gene. The downregulation of the HO-1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO-1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO-1 gene expression in AML cells and its expression suppresses their survival by downregulating HO-1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy. (Cancer Sci 2010)
Cancer Science 03/2010; 101(6):1409 - 1416. · 3.33 Impact Factor
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Takuya Miyazaki,
Yohei Kirino,
Mitsuhiro Takeno,
Maasa Hama,
Ayumi Ushihama,
Reina Watanabe,
Kaoru Takase,
Takayoshi Tachibana,
Kenji Matsumoto,
Masatsugu Tanaka, Satoshi Yamaji,
Haruko Ideguchi,
Naoto Tomita,
Hiroyuki Fujita,
Shigeru Ohno,
Atsuhisa Ueda,
Yoshiaki Ishigatsubo
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ABSTRACT: Heme oxygenase (HO)-1, a heme-degrading enzyme inducible by various stimuli, plays a key role in the regulation of inflammatory response in monocytes/macrophages. The serum HO-1 level is remarkably increased in patients with secondary hemophagocytic syndrome (HPS) or adult-onset Still's disease. We measured serum HO-1 levels in patients with a variety of hematological diseases, including secondary HPS, by means of ELISA. Serum HO-1 levels were significantly higher in 22 patients with HPS (134.7 +/- 116.2 ng/mL, P < 0.0001) at diagnosis than in 80 patients with other hematological diseases. The most effective cutoff point between HPS and other conditions was 14.5 ng/mL, with 100.0% sensitivity and 96.3% specificity. In HPS patients, the serum HO-1 levels showed the highest correlation with serum ferritin (r = 0.682, P = 0.0005), which reflects the disease activity of HPS. Moreover, both HO-1 and ferritin levels were reduced in parallel after successful treatment in patients with HPS, irrespective of underlying diseases. However, HO-1 levels were not elevated in patients with other causes of hyperferritinemia. These data demonstrate that serum HO-1 can distinguish secondary HPS from other hematological diseases, including those associated with hyperferritinemia.
International journal of hematology 03/2010; 91(2):229-37. · 1.17 Impact Factor
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Takuya Miyazaki,
Yohei Kirino,
Mitsuhiro Takeno,
Sei Samukawa,
Maasa Hama,
Masatsugu Tanaka, Satoshi Yamaji,
Atsuhisa Ueda,
Naoto Tomita,
Hiroyuki Fujita,
Yoshiaki Ishigatsubo
[show abstract]
[hide abstract]
ABSTRACT: Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO-1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid-derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO-1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO-1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or gamma-interferon, they significantly expressed both HO-1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO-1 expression in U937 cells but suppressed it in primary monocytes and PMA-treated U937 cells. In HO-1-expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf-recognition elements, the enhancer regions of the HO-1 gene. The downregulation of the HO-1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO-1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO-1 gene expression in AML cells and its expression suppresses their survival by downregulating HO-1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy.
Cancer Science 03/2010; 101(6):1409-16. · 3.33 Impact Factor
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ABSTRACT: Affixin/beta-parvin is an integrin-linked kinase (ILK)-binding focal adhesion protein highly expressed in skeletal muscle and heart. To elucidate the possible role of affixin in skeletal muscle, we established stable C2C12 cell line expressing T7-tagged human affixin (C2C12-affixin cells). Exogenous expression of affixin promotes lamellipodium formation where affixin, ILK alphap21-activated kinase (PAK)-interactive exchange factor (PIX) and betaPIX accumulate. The association of affixin and betaPIX was confirmed by immunoprecipitation and pull down assay. In C2C12-affixin cells, an increased level of activated Rac1 but not Cdc42 was observed, and mutant betaPIX lacking guanine nucleotide exchange factor activity inhibited lamellipodium formation. These results suggest that affixin is involved in reorganization of subsarcolemmal cytoskeletal actin by activation of Rac1 through alpha and betaPIXs in skeletal muscle.
FEBS Letters 05/2008; 582(8):1189-96. · 3.54 Impact Factor
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ABSTRACT: Cell adhesion signaling via the integrin-extracellular matrix connection plays a critical role in the growth and survival of normal adhering cells. Integrin-linked kinase is a ubiquitously expressed serine-threonine protein kinase capable of interacting with the cytoplasmic domains of integrin beta1 and beta3 and plays a critical role of an interface between integrin and the cytoskeleton in integrin-dependent cell adhesion, spreading, and cell shape change. In this study, we evaluated integrin beta1, integrin-linked kinase, and phosphorylated-Akt (Ser 473; pAkt) expressions in 118 consecutive non-small cell lung cancer tissue samples surgically resected between 1997 and 2000. As a result, we identified the specific subset of strong membranous staining of integrin beta1, strong cytoplasmic staining of integrin-linked kinase, and strong cytoplasmic staining with a granular pattern of pAkt in the non-small cell lung cancer tissue samples. In addition, we provide evidence that integrin-linked kinase, integrin beta1, and the activated form of Akt are mutually associated with poor prognosis in non-small cell lung cancer and that the simultaneous overexpression of these proteins is an independent prognostic factor (hazard ratio, 2.771; P = .003) comparable with standard prognostic factors such as T factor and lymphatic invasion by multivariate analysis. Thus, further studies of the integrin beta1-integrin-linked kinase-pAkt signaling pathway may provide a novel prognostic marker and therapeutic target for non-small cell lung cancer.
Human Pathlogy 08/2007; 38(7):1081-91. · 2.88 Impact Factor
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ABSTRACT: It has been reported in the Western literature that patients with chronic renal disease have developed anti-erythropoietin (EPO) antibody-related pure red cell aplasia (PRCA). To investigate the incidence of anti-EPO antibody-related PRCA in Japan, we designed a questionnaire survey based on previous reports of patients who had PRCA during treatment with EPO. Thirteen of 17 patients were evaluated in this study. In all 13 patients, EPO delivery was via injection, 9 subcutaneously, 2 intravenously and 2 with a combination of the 2 methods. Three of 4 patients treated with subcutaneous EPO administration were positive for anti-EPO antibodies, but all patients treated by intravenous injection were negative. The EPO was stopped in 8 patients after the onset of PRCA, and immunosuppressive therapy with prednisolone and/or cyclosporine was administered in 12 patients. An improvement in PRCA was obtained in 12 patients. It was suspected that previous reports in Japan may have included both anti-EPO antibody-associated PRCA and incidental cases. Furthermore, subcutaneous administration of EPO may effect the production of anti-EPO antibodies.
[Rinshō ketsueki] The Japanese journal of clinical hematology 06/2007; 48(5):391-6.
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ABSTRACT: We report on a 70-year-old male who developed cavernous sinus syndrome as the initial symptom of multiple myeloma. He was admitted with diplopia and ptosis in October 2004. The diagnosis of multiple myeloma and cavernous sinus syndrome due to a gross mass at the sinus base were made. Cerebral computed tomography revealed that the lesion occupied the sphenoid sinus and involved the oculomoter nerve. He underwent local irradiation of the mass followed by systemic chemotherapy. The symptoms caused by the mass disappeared after the treatment. Clinicians need to be aware of the rare manifestation of multiple myeloma.
[Rinshō ketsueki] The Japanese journal of clinical hematology 11/2006; 47(10):1393-5.
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ABSTRACT: We report a rare case of a patient with non-Hodgkin's lymphoma who developed multiple bone lesions and hypercalcemia. A 50-year-old woman complained of drowsiness and multiple bone pain on admission. Radiographic examination revealed multiple bone fractures and osteolytic lesions. She was diagnosed with diffuse large B cell lymphoma by biopsy of an inguinal lymph node. Elevation of parathyroid hormone-related protein (PTHrP) and hypercalcemia were confirmed pretreatment, and those serum levels decreased during chemotherapy for lymphoma. However, the disease was resistant to chemotherapy combined with rituximab. These findings suggest that hypercalcemia is associated with PTHrP and the prognosis of patients with bone lymphoma in advanced stage is poor, although it is thought to be a relatively favorable prognosis in localized primary lymphoma of bone.
American Journal of Hematology 07/2006; 81(6):439-42. · 4.67 Impact Factor
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ABSTRACT: Leukocyte extravasation is an important step of inflammation, in which integrins have been demonstrated to play an essential role by mediating the interaction of leukocytes with the vascular endothelium and the subendothelial extracellular matrix. Previously, we identified an integrin-linked kinase (ILK)-binding protein affixin (beta-parvin), which links initial integrin signals to rapid actin reorganization, and thus plays critical roles in fibroblast migration. In this study, we demonstrate that gamma-parvin, one of three mammalian parvin family members, is specifically expressed in several lymphoid and monocytic cell lines in a complementary manner to affixin. Like affixin, gamma-parvin directly associates with ILK through its CH2 domain and colocalizes with ILK at focal adhesions as well as the leading edge of PMA-stimulated U937 cells plated on fibronectin. The overexpression of the C-terminal fragment containing CH2 domain or the depletion of gamma-parvin by RNA interference inhibits the substrate adhesion of MCP-1-stimulated U937 cells and the spreading of PMA-stimulated U937 cells on fibronectin. Interestingly, the overexpression of the CH2 fragment or the gamma-parvin RNA interference also disrupts the asymmetric distribution of PTEN and F-actin observed at the very early stage of cell spreading, suggesting that the ILK-gamma-parvin complex is essential for the establishment of cell polarity required for leukocyte migration. Taken together with the results that gamma-parvin could form a complex with some important cytoskeletal proteins, such as alphaPIX, alpha-actinin, and paxillin as demonstrated for affixin and actopaxin (alpha-parvin), the results in this study suggest that the ILK-gamma-parvin complex is critically involved in the initial integrin signaling for leukocyte migration.
The Journal of Immunology 04/2006; 176(6):3611-24. · 5.79 Impact Factor
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ABSTRACT: This study investigated whether integrin-linked kinase (ILK) is involved in the pathogenesis of chronic glomerulonephritis (GN) by analyzing the expression and activity of glomerular ILK in a chronic rat model of mesangioproliferative GN. Double immunostaining of kidneys obtained at different time points with glomerular cell-specific markers revealed that ILK was primarily expressed by glomerular epithelial cells, and weakly by mesangial cells (MCs) and endothelial cells in control rats, but dramatically increased in a typical mesangial pattern at days 21 and 28 of GN. Semiquantitative assessment indicated that the level of glomerular ILK expression closely parallels the level of accumulation of glomerular extracellular matrix (ECM) as well as fibronectin (FN). Immunoprecipitation and kinase activity assays using isolated nephritic glomeruli indicated a striking increase of ILK activity on days 21 and 28 of GN. Further, cultured rat MCs overexpressing kinase-deficient ILK diminished FN assembly and collagen matrix remodeling as compared with control transfectants. The results showed that glomerular ILK expression and activity are markedly increased in an experimental model of chronic GN. Increased activity of ILK in MCs may contribute to the development of chronic mesangial alterations leading to glomerular scarring.
Life Sciences 04/2006; 78(16):1794-800. · 2.53 Impact Factor
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ABSTRACT: A 31-year-old man was diagnosed as having cutaneous T-cell lymphoma in January 1994. He received an allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor in May 1995, because of refractoriness to chemotherapy. The patient had been treated with immunosuppressants including prednisolone and cyclosporin A for chronic graft-versus-host disease (GVHD) of the extensive type following acute GVHD. Five years after the BMT, he developed moderately differentiated squamous cell carcinoma (SCC) on the mandibular gingival mucosa and underwent surgical resection. Furthermore, 6 years after the BMT well differentiated SCC developed on his palate and was resected. Concurrently, he was diagnosed as having esophageal cancer (poorly differentiated SCC) and underwent a subtotal esophagotomy. One year later he had a recurrence of the esophageal cancer with dysphagia and was treated with radiation and chemotherapy. He remains free of triple cancer and lymphoma. It is suggested that total body irradiation, immunosuppressants, and chronic GVHD are associated with a risk of secondary malignancies following allogeneic BMT. These factors might have contributed to the onset of triple cancer in our patient.
[Rinshō ketsueki] The Japanese journal of clinical hematology 08/2005; 46(7):496-500.
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ABSTRACT: We report a patient with chronic lymphocytic leukemia (CLL) who developed idiopathic thrombocytopenic purpura (ITP) and myasthenia gravis (MG) after fludarabine therapy. ITP developed after 6 cycles of fludarabine treatment, and MG occurred 2 months after the onset of ITP. MG was successfully treated with immunosuppressive therapy and plasma exchange, while rituximab was effective for CLL and ITP. Fludarabine seemed to have an important role in the onset of ITP and MG in this case.
Leukemia and Lymphoma 08/2005; 46(7):1101-2. · 2.58 Impact Factor
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ABSTRACT: The dysferlin gene is defective in Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin is a sarcolemmal protein that is implicated in calcium-dependent membrane repair. Affixin (beta-parvin) is a novel, integrin-linked kinase-binding protein that is involved in the linkage between integrin and the cytoskeleton. Here we show that affixin is a dysferlin binding protein that colocalizes with dysferlin at the sarcolemma of normal human skeletal muscle. The immunoreactivity of affixin was reduced in sarcolemma of MM and LGMD2B muscles, although the total amount of the affixin protein was normal. Altered immunoreactivity of affixin was also observed in other muscle diseases including LGMD1C, where both affixin and dysferlin showed quite similar changes with a reduction of sarcolemmal staining with or without cytoplasmic accumulations. Colocalization of dysferlin and affixin was confirmed by immunofluorescence analysis using dysferlin-expressing C2 myoblasts. Wild-type and mutant dysferlin colocalized with endogenous affixin. The interaction of dysferlin and affixin was confirmed by immunoprecipitation study using normal human and mouse skeletal muscles. Using immunoprecipitation with deletion mutants of dysferlin, we have identified that C-terminal region of dysferlin is an apparent binding site for affixin. We also found N-terminal calponin homology domain of affixin as a binding site for dysferlin. Our results suggest that affixin may participate in membrane repair with dysferlin.
Journal of Neuropathology and Experimental Neurology 05/2005; 64(4):334-40. · 4.26 Impact Factor
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Maki Takabayashi,
Heiwa Kanamori,
Hirotaka Takasaki, Satoshi Yamaji,
Hideyuki Koharazawa,
Jun Taguchi,
Naoto Tomita,
Katsumichi Fujimaki,
Shin Fujisawa,
Atsuo Maruta,
Yoshiaki Ishigatsubo
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ABSTRACT: We monitored cytokine-secreting cells using an enzyme-linked immunospot (ELISPOT) assay in a prospective study to assess the cytokine network after transplantation.
Peripheral blood mononuclear cells were collected from 23 patients who received allogeneic stem cell transplantation, from before the preconditioning regimen to 56 days after transplantation. The number of interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha)-secreting cells were measured by ELISPOT assay. For IL-4 and IFN-gamma, in vitro stimulation with phorbol 12-myristate 13-acetate and phytohemagglutinin was performed.
The frequency of IL-4-secreting cells was significantly higher in five patients receiving peripheral blood stem cell transplantation (PBSCT) than that in 18 patients who received bone marrow transplantation (BMT). Based on IFN-gamma and TNF-alpha release, there was a trend toward a decrease in the number of cytokine-secreting cells in PBSCT compared with BMT. Furthermore, patients who did not develop acute graft-vs-host disease (GVHD, n=5) showed a significantly higher number of IL-4-secreting cells compared with those who developed acute GVHD (n=18). Both IFN-gamma-secreting cells and TNF-alpha-secreting cells showed a trend to increase in number in patients with acute GVHD. In patients who received reduced-intensity stem cell transplantation (n=7) compared with conventional stem cell transplantation (n=16), there was a large number of cytokine-secreting cells detected by IL-4 and IFN-gamma release.
These results are consistent with the hypothesis that IL-4-producing cells inhibit the development of acute GVHD. In addition, the increased percentage of IL-4-secreting cells may be responsible for the unexpected low incidence of acute GVHD in PBSCT, despite the presence of large numbers of mature T cells in the donor infusion.
Experimental Hematology 03/2005; 33(2):251-7. · 2.90 Impact Factor
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ABSTRACT: An 84-year-old man was diagnosed as having pulmonary MALT lymphoma in January 1997. Six years later, he was admitted to our hospital with coughing and dyspnea in November 2003. Dissemination of MALT lymphoma was confirmed by findings of pleural effusion and bone marrow aspiration. A FISH analysis of cells from the pleural effusion revealed t(11;18)(q21;q21) and the serum level of IgM was 8,600 mg/dl (M-protein). The diagnosis of secondary macroglobulinemia was made. The patient received rituximab monotherapy because he was very elderly. Pleural effusion has not been seen after the administration of rituximab, although there have been no changes in the lung mass and serum values of M-protein.
[Rinshō ketsueki] The Japanese journal of clinical hematology 03/2005; 46(2):144-6.
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ABSTRACT: We retrospectively evaluated the outcomes in patients older than 50 years of age who underwent allogeneic hematopoietic transplantation. Twenty-three patients received conventional stem cell transplantation (CST) and 9 patients received reduced intensity stem cell transplantation (RIST). Regimen-related toxicity was observed in 21 (91%) patients with CST and 4 (44%) patients with RIST. Early death occurred within 100 days after transplantation in 6 patients with CST and 2 patients with RIST. Among the patients with complete remission, the two-year probability rate of survival was 44% in patients with CST and 100% in patients with RIST (p=0.08). Among the patients without complete remission, the two-year probability rate of survival was 30% in patients with CST and 0% in those with RIST (p=0.08). For patients receiving RIST without complete remission, relapse and infection were the main causes of death. Our data suggest that patients without complete remission should receive CST to the degree possible.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2005; 32(1):47-51.
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ABSTRACT: A 65-year-old man was diagnosed with chronic myeloid leukemia (CML) in February 1990, and was treated with busulfan and ubenimex. Cytogenetic analysis of the bone marrow revealed the Philadelphia (Ph) chromosome in 100% of cells of analyzed at diagnosis. Treatment with busulfan was stopped in March 1993 due to bone marrow suppression. The Ph chromosome was seen in 80% of cells in June 1993. He received ubenimex monotherapy after cessation of busulfan. Complete disappearance of the Ph chromosome was confirmed in May 1995 and has continued to date. This suggests that ubenimex might specifically affect the Ph chromosome and be useful as maintenance therapy for CML.
Anti-Cancer Drugs 09/2004; 15(7):729-31. · 2.41 Impact Factor
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Satoshi Yamaji,
Atsushi Suzuki,
Heiwa Kanamori,
Wataru Mishima,
Ryusuke Yoshimi,
Hirotaka Takasaki,
Maki Takabayashi,
Katsumichi Fujimaki,
Shin Fujisawa,
Shigeo Ohno,
Yoshiaki Ishigatsubo
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ABSTRACT: The linking of integrin to cytoskeleton is a critical event for an effective cell migration. Previously, we have reported that a novel integrin-linked kinase (ILK)-binding protein, affixin, is closely involved in the linkage between integrin and cytoskeleton in combination with ILK. In the present work, we demonstrated that the second calponin homology domain of affixin directly interacts with alpha-actinin in an ILK kinase activity-dependent manner, suggesting that integrin-ILK signaling evoked by substrate adhesion induces affixin-alpha-actinin interaction. The overexpression of a peptide corresponding to the alpha-actinin-binding site of affixin as well as the knockdown of endogenous affixin by small interference RNA resulted in the blockade of cell spreading. Time-lapse observation revealed that in both experiments cells were round with small peripheral blebs and failed to develop lamellipodia, suggesting that the ILK-affixin complex serves as an integrin-anchoring site for alpha-actinin and thereby mediates integrin signaling to alpha-actinin, which has been shown to play a critical role in actin polymerization at focal adhesions.
The Journal of Cell Biology 06/2004; 165(4):539-51. · 10.26 Impact Factor
