SIRP-alpha-CD47 system functions as an intercellular signal in the renal glomerulus.
The renal glomerulus consists of endothelial cells, podocytes, and mesangial cells. These cells cooperate with each other for glomerular filtration; however, the intercellular signaling molecules between glomerular cells are not fully determined. Tyrosine phosphorylation of slit diaphragm molecules is a key to the detection of the signal to podocytes from other cells. Although src kinase is involved in this event, the molecules working for dephosphorylation remain unclear. We demonstrate that signal-inhibitory regulatory protein (SIRP)-alpha, which recruits a broadly distributed tyrosine dephosphorylase SHP-2 to the plasma membrane, is located in podocytes. SIRP-alpha is a type I transmembrane glycoprotein, which has three immunoglobulin-like domains in the extracellular region and two SH2 binding motifs in the cytoplasm. This molecule functions as a scaffold for many proteins, especially the SHP-2 molecule. SIRP-alpha is concentrated in the slit diaphragm region of normal podocytes. CD47, a ligand for SIRP-alpha, is also expressed in the glomerulus. CD47 is located along the plasma membrane of mesangial cells, but not on podocytes. CD47 is markedly decreased during mesangiolysis, but increased in mesangial cells in the restoration stage. SIRP-alpha is heavily tyrosine phosphorylated under normal conditions; however, tyrosine phosphorylation of SIRP-alpha was markedly decreased during mesangiolysis induced by Thy1.1 monoclonal antibody injection. It is known that the cytoplasmic domain of SIPR-alpha is dephosphorylated when CD47 binds to the extracellular domain of SIRP-alpha. The data suggest that the CD47-SIRP-alpha interaction may be functionally important in cell-cell communication in the diseased glomerulus.
Kurihara
Hidetake
H
Department of Anatomy, Juntendo University School of Medicine, Tokyo, Japan. hidetake@juntendo.ac.jp
Harita
Yutaka
Y
Ichimura
Koichiro
K
Hattori
Seisuke
S
Sakai
Tatsuo
T
D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D051928:CD47 Antigen / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D004727:Endothelium / Q000166:cytology / Q000502:physiology; D005920:Glomerular Mesangium / Q000166:cytology / Q000502:physiology; D007678:Kidney Glomerulus / Q000166:cytology / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D050199:Podocytes / Q000166:cytology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D000943:Antigens, Differentiation; D051928:CD47 Antigen; D011971:Receptors, Immunologic; C501924:Sirpa protein, rat