Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Umemori, Hisashi; Sanes, Joshua R.

doi:10.1074/jbc.m805729200

Cited by 48 publications

(50 citation statements)

References 57 publications

(80 reference statements)

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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: 80%

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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Section: Discussionsupporting

confidence: 80%

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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“…Again in the nervous system, a soluble version of SIRPα was identified biochemically as a component with presynaptic organizer activity [39]. Only part of this activity could be inhibited with CD47 suggesting a novel interaction.…”

Section: When Are Interactions Between Sirpα and Cd47 Functional? Effmentioning

confidence: 99%

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Barclay

2009

Current Opinion in Immunology

101

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SummarySIRPα is an inhibitory receptor present on myeloid cells that interacts with a widely distributed membrane protein CD47. The activating member SIRPβ, despite extensive sequence similarity to SIRPα in the extracellular region, shows negligible binding to CD47. The SIRPα / CD47 interaction is unusual in that it can lead to bidirectional signalling through both SIRPα and CD47. This review concentrates on the interactions of SIRPα with CD47 where recent data have shed light on the structure of the proteins including determining why the activating SIRPβ does not bind CD47, evidence of extensive polymorphisms and implication for the evolution and function of this protein and paired receptors in general. The interaction may be modified by endocytosis of the receptors, cleavage by proteolysis and through interactions of surfactant proteins.

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“…Screens for a synaptic vesicle clustering activity in cultured chick motoneurons led to the identification of novel proteins involved in presynaptic differentiation: fibroblast growth factors (FGFs) and signal regulatory proteins (SIRPS) isolated from mouse brains, and collagens from the electric organ of marine rays (Umemori et al, 2004;Umemori and Sanes, 2008) (Fig. 6B).…”

Section: Fgf Laminin and Collagenmentioning

confidence: 99%

To build a synapse: signaling pathways in neuromuscular junction assembly

2010

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SummarySynapses, as fundamental units of the neural circuitry, enable complex behaviors. The neuromuscular junction (NMJ) is a synapse type that forms between motoneurons and skeletal muscle fibers and that exhibits a high degree of subcellular specialization. Aided by genetic techniques and suitable animal models, studies in the past decade have brought significant progress in identifying NMJ components and assembly mechanisms. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues, which shed light on synaptogenesis in the brain and contribute to a better understanding of muscular dystrophy. Key words: Neural development, Neuromuscular junction, Retrograde signaling, Synapse formation IntroductionThe brain contains billions of nerve cells, or neurons, which receive and integrate signals from the environment, and which govern the body's responses. Nervous system activity is made possible by synapses, contacts formed either between neurons or between a neuron and a target cell. Synapses are asymmetric structures in which neurotransmitter molecules are released from the presynaptic membrane and activate receptors on the postsynaptic membrane, thus establishing neuronal communication. As such, synapses are fundamental units of neural circuitry and enable complex behaviors. The neuromuscular junction (NMJ) is a type of synapse formed between motoneurons and skeletal muscle fibers. Large and easily accessed experimentally, this peripheral synapse has contributed greatly to the understanding of the general principles of synaptogenesis and to the development of potential therapeutic strategies for muscular disorders. The NMJ uses different neurotransmitters in different species; for example, acetylcholine (ACh) in vertebrates and glutamate in Drosophila, both of which are excitatory and cause muscle contraction. In Caenorhabditis elegans, there are two types of NMJs: at excitatory NMJs, ACh causes muscle contraction, whereas inhibitory NMJs release g-aminobutyric acid (GABA) to cause muscle relaxation. Motor nerve terminals differentiate to form presynaptic active zones, where synaptic vesicles dock and release neurotransmitters. On the apposed postsynaptic membranes, neurotransmitter receptors are packed at high densities. Aided by genetic techniques and by the use of suitable animal models, including rodents, zebrafish, Drosophila and C. elegans, studies in the past decade have brought significant progress, not only in identifying components present in pre-and postsynaptic membranes, but also in understanding the mechanisms that underpin NMJ assembly. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues from motor nerves and muscle fibers. Readers are referred to other outstanding reviews for a broad view of NMJ development (see Froehner, 1993;Hall and Sanes, 1993;Kummer et al., 2006;Salpeter and Loring, 1985;Schaeffer et al., 2001). NMJ formati...

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Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Cited by 48 publications

References 57 publications

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

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

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

To build a synapse: signaling pathways in neuromuscular junction assembly

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