Functional analysis of SIRPα in the growth cone

Wang, Xiaoxin X.; Pfenninger, Karl H.

doi:10.1242/jcs.02710

Cited by 16 publications

(17 citation statements)

References 88 publications

(124 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, a physiological substrate that allows for integrin affinity regulation, such as laminin, seems to be necessary for growth cone collapse. Because motility involves cycles of adhesion and detachment, this result is consistent with our finding that growth cones advance much more slowly on polylysine than on laminin (Wang and Pfenninger, 2006). This observation raised the issue of whether growth cone adhesions undergo redistribution when asymmetrically exposed to a repellent.…”

Section: Growth Cone Turning and Collapse Involves Regulation Of Adhesupporting

confidence: 89%

Myristoylated, Alanine-rich C-Kinase Substrate Phosphorylation Regulates Growth Cone Adhesion and Pathfinding

Gatlin

Estrada-Bernal

Sanford

et al. 2006

MBoC

Self Cite

View full text Add to dashboard Cite

Repellents evoke growth cone turning by eliciting asymmetric, localized loss of actin cytoskeleton together with changes in substratum attachment. We have demonstrated that semaphorin-3A (Sema3A)-induced growth cone detachment and collapse require eicosanoid-mediated activation of protein kinase C (PKC) and that the major PKC target is the myristoylated, alanine-rich C-kinase substrate (MARCKS). Here, we show that PKC activation is necessary for growth cone turning and that MARCKS, while at the membrane, colocalizes with ␣ 3 -integrin in a peripheral adhesive zone of the growth cone. Phosphorylation of MARCKS causes its translocation from the membrane to the cytosol. Silencing MARCKS expression dramatically reduces growth cone spread, whereas overexpression of wild-type MARCKS inhibits growth cone collapse triggered by PKC activation. Expression of phosphorylation-deficient, mutant MARCKS greatly expands growth cone adhesion, and this is characterized by extensive colocalization of MARCKS and ␣ 3 -integrin, resistance to eicosanoid-triggered detachment and collapse, and reversal of Sema3A-induced repulsion into attraction. We conclude that MARCKS is involved in regulating growth cone adhesion as follows: its nonphosphorylated form stabilizes integrin-mediated adhesions, and its phosphorylation-triggered release from adhesions causes localized growth cone detachment critical for turning and collapse.

show abstract

Section: Growth Cone Turning and Collapse Involves Regulation Of Adhesupporting

confidence: 89%

Myristoylated, Alanine-rich C-Kinase Substrate Phosphorylation Regulates Growth Cone Adhesion and Pathfinding

Gatlin

Estrada-Bernal

Sanford

et al. 2006

MBoC

Self Cite

View full text Add to dashboard Cite

show abstract

“…These results and our previous observation that MuSK-induced tyrosine dephosphorylation of prepatterned AChR clusters occurs in Xenopus muscle cells after *60 min suggest that agrin's rapid activation of MuSK is followed by that of src/abl kinases and leads to enhanced SIRPa1 tyrosine phosphorylation and Shp2 signaling. SIRPa1 activates Shp2 in other types of cells, such as neurons (Wang and Pfenninger, 2006) and also smooth muscle cells, where SIRPa1-activated Shp2 regulates the dephosphorylation of insulin-like growth factor I receptor (IGF-IR) and thereby the temporal effects of IGF-1 (Maile and Clemmons, 2002). Moreover, SIRPa1 becomes tyrosine phosphorylated and associates with Shp2 during myogenic differentiation of the C2 myotubes (Kontaridis et al, 2001), and SIRPa1 has been localized at the NMJ where its expression increased after denervation (Mitsuhashi et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Regulation of ACh receptor clustering by the tyrosine phosphatase Shp2

Zhao

Qian

Chan

et al. 2007

Developmental Neurobiology

View full text Add to dashboard Cite

At the vertebrate neuromuscular junction (NMJ), postsynaptic aggregation of muscle acetylcholine receptors (AChRs) depends on the activation of MuSK, a muscle-specific tyrosine kinase that is stimulated by neural agrin and regulated by muscle-intrinsic tyrosine kinases and phosphatases. We recently reported that Shp2, a tyrosine phosphatase containing src homology two domains, suppressed MuSK-dependent AChR clustering in cultured myotubes, but how this effect of Shp2 is controlled has remained unclear. In this study, biochemical assays showed that agrin-treatment of C2 mouse myotubes enhanced the tyrosine phosphorylation of signal regulatory protein alpha1 (SIRPalpha1), a known activator of Shp2, and promoted SIRPalpha1's interaction with Shp2. Moreover, in situ experiments revealed that treatment of myotubes with the Shp2-selective inhibitor NSC-87877 increased spontaneous and agrin-induced AChR clustering, and that AChR clustering was also enhanced in myotubes ectopically expressing inactive (dominant-negative) Shp2; in contrast, AChR clustering was reduced in myotubes expressing constitutively active Shp2. Significantly, expression of truncated (nonShp2-binding) and full-length (Shp2-binding) forms of SIRPalpha1 in myotubes also increased and decreased AChR clustering, respectively, and coexpression of truncated SIRPalpha1 with active Shp2 and full-length SIRPalpha1 with inactive Shp2 reversed the actions of the exogenous Shp2 proteins on AChR clustering. These results suggest that SIRPalpha1 is a novel downstream target of MuSK that activates Shp2, which, in turn, suppresses AChR clustering. We propose that an inhibitory loop involving both tyrosine kinases and phosphatases sets the level of agrin/MuSK signaling and constrains it spatially to help generate high-density AChR clusters selectively at NMJs.

show abstract

“…The role of the SIRP family in the nervous system is largely unknown. SIRP-␣ might be involved in apoptosis (26,42) and promotion of neurite and filopodia formation in culture (23)(24)(25), but its in vivo function is not known. Functions of other members in the nervous system have not yet been reported, but at least SIRP-␤1 is expressed along with SIRP-␣ in muscle and brain at peak times of synaptogenesis (Fig.…”

Section: Sirp-␣ As a Novel Secreted Presynapticmentioning

confidence: 99%

“…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)(24)(25)(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).…”

mentioning

confidence: 99%

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Umemori

Sanes

2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

Functional analysis of SIRPα in the growth cone

Cited by 16 publications

References 88 publications

Myristoylated, Alanine-rich C-Kinase Substrate Phosphorylation Regulates Growth Cone Adhesion and Pathfinding

Myristoylated, Alanine-rich C-Kinase Substrate Phosphorylation Regulates Growth Cone Adhesion and Pathfinding

Regulation of ACh receptor clustering by the tyrosine phosphatase Shp2

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

Contact Info

Product

Resources

About