It is now well accepted that an important aspect of leukocyte interaction with extracellular matrix is that cell activation occurs as a result of integrin ligation by extracellular matrix proteins. There is now abundant evidence, generated from many laboratories, that extracellular matrix proteins can activate the proinflammatory functions of leukocytes in vitro and there is increasing data that this mechanism of activation contributes significantly to host defense and to pathologic states characterized by excessive idiopathic inflammation in vivo. The rationale for his project is to understand the molecular mechanisms involved in activation of leukocytes by extracellular matrix. Several years ago he found that in addition to integrins, a non-integrin protein of the phagocyte plasma membrane was required for extracellular matrix-induced activation. He called this IgV superfamily member with multiple transmembrane segments Integrin-Associated Protein (IAP) because of its physical and functional association with phagocyte integrins. Over the course of this project, Dr. Brown has cloned IAP ligands, made an IAP knockout mouse by targeted gene disruption and studied its host defense, set up appropriate models for studying IAP signal transduction, and demonstrated IAP association with heterotrimeric G proteins and with a novel family of cytoskeletal proteins that link IAP to intermediate filaments. Dr. Brown proposes to continue this work in the next project period by extending these in vitro and in vivo studies to understand the molecular basis for the role of IAP in leukocyte activation. Specifically, he proposes to determine i) how the multiple membrane-spanning domain influences IAP ligand binding and signaling; ii) the mechanism and significance of IAP interaction with intermediate filaments; and iii) how IAP regulates transendothelial leukocyte migration. These studies will contribute greatly to the understanding and ultimately the control of the inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038330-18
Application #
6625061
Study Section
Special Emphasis Panel (ZRG1-IMS (01))
Program Officer
Marino, Pamela
Project Start
1986-12-01
Project End
2003-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
18
Fiscal Year
2003
Total Cost
$319,250
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Su, Xiao; Johansen, Mette; Looney, Mark R et al. (2008) CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia. J Immunol 180:6947-53
Johansen, Mette L; Brown, Eric J (2007) Dual regulation of SIRPalpha phosphorylation by integrins and CD47. J Biol Chem 282:24219-30
Rebres, Robert A; Kajihara, Kimberly; Brown, Eric J (2005) Novel CD47-dependent intercellular adhesion modulates cell migration. J Cell Physiol 205:182-93
N'Diaye, Elsa-Noah; Brown, Eric J (2003) The ubiquitin-related protein PLIC-1 regulates heterotrimeric G protein function through association with Gbetagamma. J Cell Biol 163:1157-65
Rebres, R A; Vaz, L E; Green, J M et al. (2001) Normal ligand binding and signaling by CD47 (integrin-associated protein) requires a long range disulfide bond between the extracellular and membrane-spanning domains. J Biol Chem 276:34607-16
Green, J M; Zhelesnyak, A; Chung, J et al. (1999) Role of cholesterol in formation and function of a signaling complex involving alphavbeta3, integrin-associated protein (CD47), and heterotrimeric G proteins. J Cell Biol 146:673-82
Blystone, S D; Slater, S E; Williams, M P et al. (1999) A molecular mechanism of integrin crosstalk: alphavbeta3 suppression of calcium/calmodulin-dependent protein kinase II regulates alpha5beta1 function. J Cell Biol 145:889-97
Lindberg, F P; Gresham, H D; Reinhold, M I et al. (1996) Integrin-associated protein immunoglobulin domain is necessary for efficient vitronectin bead binding. J Cell Biol 134:1313-22
Blystone, S D; Lindberg, F P; Williams, M P et al. (1996) Inducible tyrosine phosphorylation of the beta3 integrin requires the alphaV integrin cytoplasmic tail. J Biol Chem 271:31458-62
Lindberg, F P; Bullard, D C; Caver, T E et al. (1996) Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274:795-8

Showing the most recent 10 out of 48 publications