Ectodomain Shedding of SHPS-1 and Its Role in Regulation of Cell Migration

Ohnishi, Hiroshi; Kobayashi, Hill Hiroki; Okazawa, Hideki; Ohe, Yoshihide; Tomizawa, Kyoko; Sakakibara, Ryuji; Matozaki, Takashi

doi:10.1074/jbc.m313085200

Cited by 31 publications

(32 citation statements)

References 48 publications

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“…These results verify that cells cleave and release the extracellular domain of SIRP-␣, which is consistent with a previous study with Chinese hamster ovary cells (31). We next examined whether tissues express both full-length and truncated forms of SIRP-␣.…”

Section: Table 1 Purification Of Presynaptic Organizing Molecules Frosupporting

confidence: 91%

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Umemori

Sanes

2008

Journal of Biological Chemistry

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Neurons transmit information to each other at functional contact sites called synapses. Information transfer involves release of neurotransmitters from synaptic vesicles in nerve terminals, binding of neurotransmitter by receptors at the precisely apposed postsynaptic membrane, and generation of an electrical or chemical signal in the postsynaptic cell. Alterations in synapse number and strength underlie neural plasticity, and defects in synaptic circuitry and function underlie some neurological disorders. Thus, proper assembly of appropriate synapses is essential for optimal functioning of the nervous system (1, 2).Pre-and postsynaptic specializations form in precise apposition to each other at sites where axons contact specific target cells. This precision is one indication that signals are exchanged between presynaptic neurons and postsynaptic target cells to organize synaptic differentiation and maturation (3-5). Several molecules have been identified that function as "synaptic organizers" in cultured neurons, and over the past few years, a few have been shown to function in vivo in the mammalian brain (6 -9). The brain contains dozens if not hundreds of different synaptic types, however, and additional organizers likely remain to be identified.To identify novel synaptic organizers, we devised an assay for presynaptic differentiation in isolated, cultured neurons, and used it to guide biochemical purification of active molecules from brain extracts. In initial studies, we showed that fibroblast growth factor (FGF) 2 22 and its close relatives, FGFs 7 and 10, promote differentiation of neuromuscular and cerebellar synapses (7, 10). Some neuronal populations were unresponsive to these FGFs, however, and FGFs accounted for less than half of the active material in brain extracts. We therefore sought additional active species. Here, we show that SIRP-␣ is a presynaptic organizer.SIRP-␣ (signal regulatory protein ␣; also known as PTPNS1, SHPS1, CD172a, BIT, MFR, and p84) is a transmembrane protein with three immunoglobulin domains (11-14). SIRP-␣ is highly expressed in neurons and myeloid cells, and is concentrated at synapses in the brain (11-18). Its intracellular domain has tyrosine residues that, when phosphorylated, can interact with phosphatases to send negative signals downstream. SIRP-␣ is involved in hematopoietic cell functions such as regulation of host cell phagocytosis and clearance, inflammatory mediator production, and control of cell migration (11-13, 19 -22). Little is known about roles of SIRP-␣ in the nervous system, but it is expressed by hippocampal neurons, promotes neurite outgrowth in culture, and enhances the effect of brainderived neurotrophic factor (23-26). Most of these studies, however, focused on intracellular signals transduced by SIRP-␣ when it is engaged by its ligand, CD47/integrin-associated protein (16). Here, in contrast, we show that the extracellular domain of SIRP-␣ is cleaved and acts as a secreted presynaptic organizer. We also show that two little-studied close relative...

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Section: Table 1 Purification Of Presynaptic Organizing Molecules Frosupporting

confidence: 91%

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Umemori

Sanes

2008

Journal of Biological Chemistry

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“…It is probable that SIRP␣ dimers on the cell surface acting as a bivalent receptor can bind two CD47 molecules in trans in a manner reminiscent of the interaction between B7-1/2 and CD28/ CTLA4, in which the interaction of ligand dimers with receptor dimers is enhanced by increased avidity (61). Furthermore, this model is consistent with reported observations of "synapselike" structures between SIRP␣-expressing macrophages and CD47-expressing red blood cells that inhibited phagocytosis (49,62,63).…”

Section: Discussionsupporting

confidence: 86%

The Role of cis Dimerization of Signal Regulatory Protein α (SIRPα) in Binding to CD47

Lee

Weber

Laur

et al. 2010

Journal of Biological Chemistry

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Interaction of SIRP␣ with its ligand, CD47, regulates leukocyte functions, including transmigration, phagocytosis, oxidative burst, and cytokine secretion. Recent progress has provided significant insights into the structural details of the distal IgV domain (D1) of SIRP␣. However, the structural roles of proximal IgC domains (D2 and D3) have been largely unstudied. The high degree of conservation of D2 and D3 among members of the SIRP family as well as the propensity of known IgC domains to assemble in cis has led others to hypothesize that SIRP␣ forms higher order structures on the cell surface. Here we report that SIRP␣ forms noncovalently linked cis homodimers. Treatment of SIRP␣-expressing cells with a membrane-impermeable cross-linker resulted in the formation of SDS-stable SIRP␣ dimers and oligomers. Biochemical analyses of soluble recombinant extracellular regions of SIRP␣, including domain truncation mutants, revealed that each of the three extracellular immunoglobulin loops of SIRP␣ formed dimers in solution. Coimmunoprecipitation experiments using cells transfected with different affinity-tagged SIRP␣ molecules revealed that SIRP␣ forms cis dimers. Interestingly, in cells treated with tunicamycin, SIRP␣ dimerization but not CD47 binding was inhibited, suggesting that a SIRP␣ dimer is probably bivalent. Last, we demonstrate robust dimerization of SIRPa in adherent, stimulated human neutrophils. Collectively, these data are consistent with SIRP␣ being expressed on the cell surface as a functional cis-linked dimer. Signal regulatory proteins (SIRPs)2 are immunoglobulin superfamily members and include SIRP␣, SIRP␤, and SIRP␥ (1, 2). Expression of SIRPs is largely restricted to leukocytes, where SIRP␣ and SIRP␤ are expressed in myeloid lineages, and SIRP␥ is expressed in lymphocytes (1, 2). Interestingly, SIRP␣ is also expressed in smooth muscle cells and neurons and has important signaling properties (3-5). The extracellular domains of SIRPs consist of a membrane-distal Ig variable-like (IgV) fold (D1), and two membrane-proximal Ig constant-like (IgC) folds (D2D3). The ectodomains of the various SIRP family members share a high degree of homology between their respective protein sequences. In contrast, the cytoplasmic signaling elements of different SIRPs differ greatly. For instance, the cytoplasmic tail of SIRP␣ contains four immunoreceptor tyrosine-based inhibitory motifs, which recruit Src homology 2 phosphatases upon phosphorylation (6). In contrast, SIRP␤ and SIRP␥ have short cytoplasmic tails that are only a few amino acids long. SIRP␤ associates with the immunoreceptor tyrosine-based activating motif containing adaptor protein DAP12 through charge interactions in the transmembrane regions (7,8). On the other hand, SIRP␥, lacking known signaling motifs, has been presumed to be a decoy receptor (9). However, a recent report suggests that SIRP␥ on T cells may be able to transmit signals that can regulate transendothelial migration (10). The major cellular ligand of SIRP␣ and SIRP␥ is CD47, a ubiquito...

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“…Interestingly, in ADAM-12-overexpressing cells, CD47 membrane expression and mRNA levels are significantly down-regulated. In addition, the ectodomain shedding of SIRPa is required for cell migration (41) and is blocked by a metalloprotease inhibitor KB-R7785, which has been shown to neutralize ADAM-12-mediated ectodomain cleavage of HB-EGF (17). Nevertheless, neutrophil coculture with BA17 and BA36 clones does not reduce the membrane expression of SIRP-a in neutrophils, suggesting that this metalloprotease is not involved in the shedding of SIRPa.…”

Section: Discussionmentioning

confidence: 99%

Role of A Disintegrin And Metalloprotease-12 in Neutrophil Recruitment Induced by Airway Epithelium

Estrella

Rocks

Paulissen

et al. 2009

Am J Respir Cell Mol Biol

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Among proteases, metalloproteases are implicated in tissue remodeling, as shown in numerous diseases including allergy. ADAMs (A Disintegrin And Metalloprotease) metalloproteases are implicated in physiologic processes such as cytokine and growth factor shedding, cell migration, adhesion, or repulsion. Our aim was to measure ADAM-12 expression in airway epithelium and to define its role during the allergic response. To raise this question, we analyzed the ADAM-12 expression ex vivo after allergen exposure in patients with allergic rhinitis and in vitro in cultured primary human airway epithelial cells (AEC). Clones of BEAS-2B cells transfected with the full-length form of ADAM-12 were generated to study the consequences of ADAM-12 up-regulation on AEC function. After allergen challenge, a strong increase of ADAM-12 expression was observed in airway epithelium from patients with allergic rhinitis but not from control subjects. In contrast with the other HB-epidermal growth factor sheddases, ADAM-10 and -17, TNF-a in vitro increased the expression of ADAM-12 by AEC, an effect amplified by IL-4 and IL-13. Up-regulation of ADAM-12 in AEC increased the expression of a3 and a4 integrins and to the modulation of cell migration on fibronectin but not on collagen. Moreover, overexpression of ADAM-12 in BEAS-2B enhanced the secretion of CXCL1 and CXCL8 and their capacity to recruit neutrophils. CD47 was strongly decreased by ADAM-12 overexpression, a process associated with a reduced adhesion of neutrophils. These effects were mainly dependent on epidermal growth factor receptor activation. In summary, ADAM-12 is produced during allergic reaction by AEC and might increase neutrophil recruitment within airway mucosa.

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Ectodomain Shedding of SHPS-1 and Its Role in Regulation of Cell Migration

Cited by 31 publications

References 48 publications

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

The Role of cis Dimerization of Signal Regulatory Protein α (SIRPα) in Binding to CD47

Role of A Disintegrin And Metalloprotease-12 in Neutrophil Recruitment Induced by Airway Epithelium

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