Macrophages of patients with X‐linked thrombocytopenia display an attenuated Wiskott‐Aldrich syndrome phenotype

Linder, Stefan; Wintergerst, Uwe; Bender‐Götze, Christine; Schwarz, Klaus; Pannicke, Ulrich; Aepfelbacher, Martin

doi:10.1046/j.0818-9641.2002.01147.x

Cited by 30 publications

(22 citation statements)

References 29 publications

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“…XLT patients express the mutant WASPs at a lower concentration than normal subjects, and the defects are observed only in platelets and not in other hemopoietic cells (43)(44)(45)(46)(47)(48). Recently, Linder et al reported that XLT macrophages, previously thought to be unaffected in this disorder, are compromised in podosome formation (49). Complex formation of mutant WASPs with WIP is impaired in XLT patients, because XLT mutations reduced WASP binding to WIP (50).…”

Section: Discussionmentioning

confidence: 99%

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Tsuboi

2007

The Journal of Immunology

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Chemotactic migration of macrophages is critical for the recruitment of leukocytes to inflamed tissues. Macrophages use a specialized adhesive structure called a podosome to migrate. Podosome formation requires the Wiskott-Aldrich syndrome protein (WASP), which is a product of the gene defective in an X-linked inherited immunodeficiency disorder, the Wiskott-Aldrich syndrome. Macrophages from WASP-deficient Wiskott-Aldrich syndrome patients lack podosomes, resulting in defective chemotactic migration. However, the molecular basis for podosome formation is not fully understood. I have shown that the WASP interacting protein (WIP), a binding partner of WASP, plays an important role in podosome formation in macrophages. I showed that WASP bound WIP to form a complex at podosomes and that the knockdown of WIP impairs podosome formation. When WASP binding to WIP was blocked, podosome formation was also impaired. When WASP expression was reduced by small interfering RNA transfection, the amount of the complex of WASP with WIP decreased, resulting in reduced podosome formation. Podosomes were restored by reconstitution of the WASP-WIP complex in WASP knockdown cells. These results indicate that the WASP-WIP complex is required for podosome formation in macrophages. When podosome formation was reduced by blocking WASP binding to WIP, transendothelial migration of macrophages, the most crucial process in macrophage trafficking, was impaired. These results suggest that a complex of WASP with WIP plays a critical role in podosome formation, thereby mediating efficient transendothelial migration of macrophages.

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Section: Discussionmentioning

confidence: 99%

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Tsuboi

2007

The Journal of Immunology

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“…XLT patients express the mutant proteins at a lower concentration than normal subjects (3,4,61,62), and defects were observed in only platelets, but not in other hemopoietic cells (3,4). Recently, Linder et al (57) reported that XLT macrophages, previously thought to be unaffected in this disorder, are compromised in podosome formation. Complex formation of mutant WASPs with verprolins is most likely impaired in XLT patients, because XLT mutations reduced WASP binding to WIP (56).…”

Section: Discussionmentioning

confidence: 99%

A Complex of Wiskott-Aldrich Syndrome Protein with Mammalian Verprolins Plays an Important Role in Monocyte Chemotaxis

Tsuboi

2006

The Journal of Immunology

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The Wiskott-Aldrich syndrome protein (WASP) is a product of the gene defective in an Xid disorder, Wiskott-Aldrich syndrome. WASP expression is limited to hemopoietic cells, and WASP regulates the actin cytoskeleton. It has been reported that monocytes/macrophages from WASP-deficient Wiskott-Aldrich syndrome patients are severely defective in chemotaxis, resulting in recurrent infection. However, the molecular basis of such chemotactic defects is not understood. Recently, the WASP N-terminal region was found to bind to the three mammalian verprolin homologs: WASP interacting protein (WIP); WIP and CR16 homologous protein (WICH)/WIP-related protein (WIRE); and CR16. Verprolin was originally found to play an important role in the regulation of actin cytoskeleton in yeast. We have shown that WASP, WIP, and WICH/WIRE are expressed predominantly in the human monocyte cell line THP-1 and that WIP and WICH/WIRE are involved in monocyte chemotaxis. When WASP binding to verprolins was blocked, chemotactic migration of monocytes was impaired in both THP-1 cells and primary human monocytes. Increased expression of WASP and WIP enhanced monocyte chemotaxis. Blocking WASP binding to verprolins impaired cell polarization but not actin polymerization. These results indicate that a complex of WASP with mammalian verprolins plays an important role in chemotaxis of monocytes. Our results suggest that WASP and mammalian verprolins function as a unit in monocyte chemotaxis and that the activity of this unit is critical to establish cell polarization. In addition, our results also indicate that the WASP-verprolin complex is involved in other functions such as podosome formation and phagocytosis.

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“…The SH3 domain of CIP4 interacts with Wiskott-Aldrich syndrome protein, a regulator of the actin cytoskeleton, whereas the amino-terminal region including the FCH domain binds to microtubules, suggesting that CIP4 is a potential linker between the actin cytoskeleton and microtubules (27). Actually, CIP4 has been shown to be involved in microtubule-dependent formation of F-actin-rich podosomal adhesion in macrophages (30). Rapostlin has two functional domains, FCH-containing amino-terminal region and SH3 domain, those of CIP4 being involved in the reorganization of both microtubules and actin filaments.…”

Section: Discussionmentioning

confidence: 99%

Rapostlin Is a Novel Effector of Rnd2 GTPase Inducing Neurite Branching

Fujita

Katoh

Ishikawa

et al. 2002

Journal of Biological Chemistry

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Rho family GTPases are central regulators of neuronal morphology. Recently, Rnd proteins, Rnd1, Rnd2, and Rnd3/RhoE, have been identified as new members of Rho family GTPases. Of these, Rnd2 is specifically expressed in neurons in brain; however, the signaling pathways of Rnd2 are not known. Here we have performed a yeast two-hybrid screen using Rnd2 as a bait and identified a novel Rnd2-effector protein, expressed predominantly in brain. We named it Rapostlin (apostle of Rnd2). Rapostlin has two functional domains, Fer-CIP4 homology (FCH) domain at the amino terminus and SH3 (Src homology 3) domain at the carboxyl terminus. In in vitro binding assays, Rapostlin specifically binds to Rnd2 among the Rho family GTPases in a GTPdependent manner, and the Rnd2-binding domain of Rapostlin is localized between FCH and SH3 domains. Rapostlin directly binds to microtubules, and the aminoterminal region containing the FCH domain of Rapostlin is essential for this interaction. In PC12 cells, Rapostlin induces neurite branching in response to Rnd2, and at least the amino-terminal region of Rapostlin is necessary for this activity. Therefore, Rapostlin is the first effector of Rnd2, regulating neurite branch formation.

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Macrophages of patients with X‐linked thrombocytopenia display an attenuated Wiskott‐Aldrich syndrome phenotype

Cited by 30 publications

References 29 publications

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages

A Complex of Wiskott-Aldrich Syndrome Protein with Mammalian Verprolins Plays an Important Role in Monocyte Chemotaxis

Rapostlin Is a Novel Effector of Rnd2 GTPase Inducing Neurite Branching

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