title: Mouse MCP1 C-terminus inhibits human MCP1-induced chemotaxis and BBB compromise.
abstract: Compared to the rodent monocyte chemoattractant protein 1 (MCP1/CCL2), the human MCP1 lacks a C-terminal extension. Although the function of this C-extension is not entirely defined, in previous work we reported that it decreases the chemotactic properties of mouse MCP1. To determine if this function is specific to the rodent chemokine, or if the C-terminal extension has the ability to regulate chemotactic potency to MCP1 in general, we generated a chimeric protein consisting of human MCP1 fused to the mouse MCP1 C-terminal fragment. We found that mouse MCP1 C-terminus significantly decreased the chemotactic potency of human MCP1 and diminished the blood brain barrier compromise normally induced by the human protein. Not only did mouse MCP1 C-terminus inhibit human MCP1-induced Rac1 activation and formation of lamellipodia, it also disrupted the staining pattern of ZO-1 at cell-cell borders and prevented human MCP1-induced F-actin formation in brain microvascular endothelial cells. Additionally, the MCP1 C-terminus dramatically decreased human MCP1-induced activation of ERM proteins in endothelial cells. These findings confirm that the rodent C-terminal MCP1 extension acts as a rheostat for MCP1 functions and suggest that potentially in humans another protein or protein complex may assume a similar regulatory function.
authors: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794-8651, USA.
authors: Yao
authors: Y
authors: Yao
authors: Stella E
authors: SE
authors: Tsirka
references: Biochemistry. 1997 Nov 4;36(44):13570-8
references: 9354625
references: J Cereb Blood Flow Metab. 2006 Jun;26(6):797-810
references: 16192992
references: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14040-5
references: 19667186
references: J Cell Biol. 2005 Aug 29;170(5):793-802
references: 16129786
references: J Cell Sci. 2011 May 1;124(Pt 9):1486-95
references: 21486949
references: Am J Physiol. 1999 May;276(5):F737-50
references: 10330056
references: Nature. 2000 Nov 9;408(6809):203-6
references: 11089974
references: J Immunol. 1994 Apr 1;152(7):3541-9
references: 8144933
references: J Biol Chem. 1997 Jun 27;272(26):16133-9
references: 9195909
references: J Neurosci. 1986 Aug;6(8):2163-78
references: 3018187
references: Nat Immunol. 2005 Sep;6(9):902-10
references: 16056228
references: Mol Cell Biol. 1995 Sep;15(9):4851-5
references: 7651403
references: J Biol Chem. 2006 Mar 31;281(13):8379-88
references: 16439355
references: Acta Neuropathol. 2001 Oct;102(4):385-92
references: 11603815
references: J Leukoc Biol. 2003 Aug;74(2):243-51
references: 12885941
references: J Biol Chem. 2010 Oct 8;285(41):31509-16
references: 20682771
references: Int J Biochem Cell Biol. 2000 Sep;32(9):931-43
references: 11084373
references: J Neurochem. 2006 May;97(4):922-33
references: 16573646
references: J Cereb Blood Flow Metab. 2005 May;25(5):593-606
references: 15689955
references: J Biol Chem. 2004 May 21;279(21):22294-305
references: 15033992
references: Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2752-6
references: 8146186
references: Neuron. 2008 May 8;58(3):325-32
references: 18466743
references: Nat Immunol. 2005 Aug;6(8):827-35
references: 15995708
references: J Neurosci. 2007 Feb 14;27(7):1738-45
references: 17301181
references: Inflamm Res. 2003 Apr;52 Suppl 1:S39-40
references: 12755402
references: J Cell Sci. 2003 Nov 15;116(Pt 22):4615-28
references: 14576355