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	<title>CD47 &#8211; Creative Biolabs Blog</title>
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	<title>CD47 &#8211; Creative Biolabs Blog</title>
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		<title>CD47-related Signaling Pathways &#038; Research Progress on the Relationship with Related Diseases (Part Three)</title>
		<link>https://www.creative-biolabs.com/blog/index.php/cd47-related-signaling-pathways-research-progress-on-the-relationship-with-related-diseases-part-three/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Mon, 12 Apr 2021 03:04:01 +0000</pubDate>
				<category><![CDATA[Biological Knowledge]]></category>
		<category><![CDATA[CD47]]></category>
		<category><![CDATA[Fusion Protein]]></category>
		<category><![CDATA[Therapeutic Antibody]]></category>
		<guid isPermaLink="false">http://www.creative-biolabs.com/blog/?p=1628</guid>

					<description><![CDATA[3 Relationship Between CD47-related Signaling Pathways and Diseases 3.1 Cancer CD47 is highly expressed on the surface of many kinds of tumor cells, which, as a signal molecule of &#8220;don&#8217;t eat me&#8221;,<a class="moretag" href="https://www.creative-biolabs.com/blog/index.php/cd47-related-signaling-pathways-research-progress-on-the-relationship-with-related-diseases-part-three/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><strong>3 Relationship Between CD47-related Signaling Pathways and Diseases</strong></p>
<p><strong>3.1 Cancer</strong></p>
<p>CD47 is highly expressed on the surface of many kinds of tumor cells, which, as a signal molecule of &#8220;don&#8217;t eat me&#8221;, interacts with SIRPα on the surface of macrophages to prevent tumor cells from being swallowed and cleared and enhance tumor viability. Therefore, targeting CD47-SIRPα interaction may be a new strategy for tumor therapy. At present, anti-tumor therapy mainly targets the CD47-SIRPα axis, and a variety of therapeutic drugs have been in clinical trials, including conventional <a href="/custom-antibody-development.html"><span style="color: #0000ff;"><strong>antibodies</strong></span></a>, fusion <a href="/Membrane-Protein-Production.html"><strong><span style="color: #0000ff;">proteins</span></strong></a>, and bispecific molecules, which block CD47 or SIRP α respectively.</p>
<p style="text-align: center;"><a href="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/The-regulatory-mechanisms-of-CD47-expression-1.jpg"><img decoding="async" fetchpriority="high" class="aligncenter  wp-image-1759" src="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/The-regulatory-mechanisms-of-CD47-expression-1.jpg" alt="" width="529" height="299" srcset="https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/The-regulatory-mechanisms-of-CD47-expression-1.jpg 652w, https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/The-regulatory-mechanisms-of-CD47-expression-1-300x169.jpg 300w" sizes="(max-width: 529px) 100vw, 529px" /></a></p>
<p style="text-align: center;">Fig. 4. The regulatory mechanisms of CD47 expression. (<em>Translational Oncology</em>)</p>
<p><strong>3.2 Cardiovascular Diseases</strong></p>
<p>The main clinical manifestations of cardiovascular diseases include stroke, macular degeneration, peripheral vascular disease, hypertension, heart, and other key organ failure, heart disease, and poor wound healing. The main cause is acute or subacute decrease of blood flow and tissue hypoperfusion, and the damage of NO signaling pathway in vascular cells is the major factor leading to cardiovascular diseases. During senescence, endogenous NO synthesis decreased while TSP1 expression increased. As mentioned earlier, the interaction between TSP1 and CD47 can inhibit the NO/cGMP signaling pathway. Therefore, inhibition of TSP1-CD47 interaction can improve NO signaling pathway and reduce the occurrence of cardiovascular diseases.</p>
<p>Kojima <em>et al</em>. found that pathological or dead smooth muscle cells and macrophages could be eliminated <em>in vitro</em> by anti-CD47 antibody, MIAP410. In different kinds of atherosclerotic mice, anti-CD47 antibody was used to block CD47 to significantly prevent the accumulation of arterial plaques and restore the clearance of diseased vascular tissue to normal.</p>
<p><strong>3.3 Autoimmune Diseases</strong></p>
<p>Studies showed that SIRPα and CD47 are associated to the formation of autoimmune diseases related to Th1 or Th17 cells, such as experimental autoimmuneencephalomyelitis (EAE), bacterial or collagen-induced arthritis, contact hypersensitivity, colitis, and Crohn&#8217;s disease. CD47-SIRPα interaction can regulate the function of DCs, especially migration and antigen presentation, which is necessary for activating autoreactive Th1 and Th17 cells. Interfering with the interaction of CD47-SIRPα can inhibit the development of arthritis, colitis, and Crohn&#8217;s disease, but in EAE it can aggravate autoimmunity. Other studies indicated that SIRPα deletion mice or anti-SIRPα antibody (P84) can significantly reduce the level of inflammation, bone erosion, and arthritis symptoms in type Ⅱ collagen arthritis mice.</p>
<p><strong>3.4 Hemophagocytic Lymphohistiocytosis </strong></p>
<p>One of the typical characteristics of hemophagocytic lymphohistiocytosis (HLH) is the enhancement of hemophagocytic function, mainly due to the impaired pathogen scavenging function of cytotoxic lymphocyte (CTL) and NK cells, resulting in excessive proliferation of macrophages and increase of hemophagocytes. The expression of CD47 in CD34+ CD38- HSCs of HLH is down-regulated, and the phagocytosis of macrophages is enhanced, resulting in hemophagocytic syndrome.</p>
<p><strong>4 Summary</strong></p>
<p>CD47 interacts with its two ligands, TSP1 and SIRPα, and participates in a variety of signal pathways, as well as a variety of physiological functions and pathological processes. Therefore, targeting CD47 provides a new method for disease treatment. At present, the treatment of targeting CD47 mainly applies in the field of anti-tumor, and the major treatment strategies are blocking antibody, recombinant fusion protein, antisense RNA, and small molecule inhibitor. There are many studies on blocking antibody and recombinant fusion protein, which mainly target CD47 and its two ligands SIRP α and TSP1. At present, the anti-tumor drugs targeting CD47 in phase I clinical trials include Hu5F9-G4, CC-90002, TTI-621, and ALX148, among which TTI-621 is a soluble recombinant SIRP α-Fc fusion protein with better penetration ability and tissue distribution, lower affinity with red blood cells, and higher safety. Small molecular inhibitors, such as peptides, have a short half-life <em>in vivo</em> and are easy to be hydrolyzed by enzymes, so they are difficult to play a therapeutic role, but can be used to design effective and stable mimic peptides, such as TSP-1 mimetic peptides, and to recognize their receptor CD36. Antisense RNA can block the translation of CD47 mRNA, thus inhibiting the expression of CD47 protein. It is also expected to become an effective means to target CD47.</p>
<p>In short, CD47 is not only a hot topic in oncology, but also plays an important role in other diseases. The development of drugs targeting CD47 is expected to provide a new strategy for the disease treatment.</p>
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		<title>CD47-related Signaling Pathways &#038; Research Progress on the Relationship with Related Diseases (Part Two)</title>
		<link>https://www.creative-biolabs.com/blog/index.php/cd47-related-signaling-pathways-research-progress-on-the-relationship-with-related-diseases-part-two/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Mon, 12 Apr 2021 02:55:24 +0000</pubDate>
				<category><![CDATA[Biological Knowledge]]></category>
		<category><![CDATA[CD47]]></category>
		<category><![CDATA[CD47 Signaling Pathways]]></category>
		<guid isPermaLink="false">http://www.creative-biolabs.com/blog/?p=1623</guid>

					<description><![CDATA[2 CD47-related Signaling Pathways The extracellular ligands interacting with CD47 are TSP1, SIRP α, and CD47 itself. Among them, little is known about the signal transduction involved in the homotypic interaction of<a class="moretag" href="https://www.creative-biolabs.com/blog/index.php/cd47-related-signaling-pathways-research-progress-on-the-relationship-with-related-diseases-part-two/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><strong>2 CD47-related Signaling Pathways</strong></p>
<p>The extracellular ligands interacting with CD47 are TSP1, SIRP α, and CD47 itself. Among them, little is known about the signal transduction involved in the homotypic interaction of CD47 itself. Therefore, at present, the main signaling pathways involved in CD47 can be roughly divided into two streams according to its ligands, that is, the signaling pathways regulated by TSP1 or SIRPα, as shown in figure 2.</p>
<p><strong>2.1 CD47/TSP-1 Signaling Pathway</strong></p>
<p>2.1.1 Regulation of G-protein Pathway</p>
<p>The complex formed by CD47 and integrin can interact with trimeric <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/g-protein-coupled-receptor-family.html">G-protein</a></strong></span> through its intracellular ligand PLIC1 to form CD47-integrin-G-protein complex. The five-transmembrane domain of CD47 and two-transmembrane fragment of integrin form a temporary seven-transmembrane complex (7TMS) that can activate G-protein. Different integrin ligands and CD47 isomers with different cytoplasmic tails can endow 7TMS complex the function of activating specific trimeric G-protein. G-protein can mediate a variety of cellular effects of CD47, such as CD47-related platelet activation requires G-protein to activate Syk kinase, thus inducing phosphorylation of Lyn and FAK. Another component of the CD47-integrin-G-protein complex is cholesterol. Cholesterol removal does not affect integrin affinity but reduces the ability of CD47 to stimulate cell adhesion to hyaluronectin. Therefore, although the basic cellular diffusion mechanism has nothing to do with cholesterol, cholesterol seems to play a necessary role in maintaining the functional CD47-integrin-G-protein complex.</p>
<p style="text-align: center;"><a href="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/123.png"><img decoding="async" class="aligncenter  wp-image-1624" src="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/123.png" alt="" width="533" height="418" srcset="https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/123.png 836w, https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/123-300x235.png 300w, https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/123-768x603.png 768w" sizes="(max-width: 533px) 100vw, 533px" /></a></p>
<p style="text-align: center;">Fig. 2. Schematic diagram of CD47/TSP-1 signaling pathways. <em>(SpringerLink)</em></p>
<p>2.1.2 Regulation of NO/cGMP Signaling Pathway</p>
<p>Endothelial NO synthase (eNOs) is the main synthase isomer of nitric oxide (NO) in vascular cells, which can convert L-arginine to L-citrulline and release NO. eNOs activity is regulated by mechanical stimulation and circulatory factors such as VEGF and acetylcholine. VEGF activates PI3K through VEGFR2 on endothelial cells, which activates protein kinase B (PKB, also known as Akt). Akt activates eNOs by phosphorylating serine 1177. At the same time, activated VEGFR2 recruits Src and induces Ca<sup>2+</sup> signaling pathway to further activate eNOs. The resulting NO binds to the heme structure of soluble guanylatecyclase (sGC) in target cells, increases its enzyme catalytic activity, leads to intracellular cGMP accumulation, and activates cGMP-dependent protein kinase (cGK1), which leads to dephosphorylation of myosin light chain and relaxation of smooth muscle. TSP1 can bind to CD47, destroy the complex of CD47 and VEGFR2, inhibit the activation of VEGFR2, and then affect the downstream signaling pathway.</p>
<p>2.1.3 Regulation of Cell Survival</p>
<p>The combination of TSP1 and CD47 can induce the transfer of BNIP3 to mitochondria. The transmembrane domain of BNIP3 can insert into the mitochondrial membrane, causing the mitochondrial permeability transition pore to open and release cytochrome C, resulting in cell death. Lack of CD47 helps cells promote their survival by activating protective autophagy pathways. Autophagy is a catabolic mechanism to maintain the stability of the internal environment, which is a process in which cytoplasmic sols and organelles are isolated into vesicles of bilayer membranes and transported to lysosomes/vacuoles for degradation, resulting in the recycling of macromolecules. Mild autophagy can prevent cells from being damaged by adverse factors and help them survive. When CD47-deficient cells were exposed to radiation, increased expression of beclin-1, ATG5, ATG7 and LC3, decreased expression of p62, and increased formation of autophagosomes can activate the protective autophagy. Among them, Beclin-1 can also bind to Bcl-2/Bcl-xL to form a complex, so the activation process of autophagy will be inhibited. Therefore, the interaction between Beclin-1 and Bcl-2 can directly control autophagy and apoptosis.</p>
<p><strong>2.2 D47/SIRPα Signaling Pathway</strong></p>
<p>2.2.1 Regulation of Phagocytosis</p>
<p>As an autologous recognition molecule, CD47 can interact with SIRPα on the surface of macrophages to prevent tumor cells and red blood cells from being cleared. This mechanism of preventing macrophage phagocytosis involves the inhibitory signaling pathway of SIRPα, which is partly through SHP-1 to inhibit macrophage phagocytosis.</p>
<p>In addition, some studies have found that the function of CD47-SIRPα interaction in erythrocyte clearance may be more complex. The senescence of human red blood cells seems to be related to the conformational change of CD47, which may rely on oxidative modification, and can change the structure of molecules from &#8220;don&#8217;t eat me&#8221; to &#8220;eat me&#8221;. Therefore, CD47 is not only a &#8220;don&#8217;t eat me&#8221; signal but may also be used as a switch to regulate the clearance of red blood cells. The abnormal expression of CD47 or SIRPα or the interference of CD47-SIRPα interaction will change the phagocytosis of macrophages and destroy the homeostasis of red blood cells.</p>
<p><a href="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/321_16176980979401.png"><img decoding="async" class="aligncenter  wp-image-1625" src="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/321_16176980979401.png" alt="" width="582" height="447" srcset="https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/321_16176980979401.png 827w, https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/321_16176980979401-300x230.png 300w, https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/321_16176980979401-768x590.png 768w" sizes="(max-width: 582px) 100vw, 582px" /></a></p>
<p style="text-align: center;">Fig. 3. Schematic diagram of CD47/SIRPα signaling pathways. <em>(Current Opinion in Immunology)</em></p>
<p>2.2.2 Regulation of <em>In Vivo</em> Homeostasis of Dendritic Cells and T Cells</p>
<p>Some studies showed that in the spleen of SIRPα mutant mice, the number of CD4+ Dendritic cells (DCs), the half-life of CD4+ DCs, and the number of CD4+ T cells all decreased, and the T cell aggregation area became smaller. It is suggested that the interaction between CD47 and SIRPα plays an important role in regulating the homeostasis of DCs and T cells <em>in vivo</em>. In addition, some studies have found that DCs and T cell responses are affected by the interaction between CD47 and SIRPα at many levels. Interference with the interaction between CD47 and SIRPα can impair the function of DCs, especially in inducing responses of helper T cells (Th1, Th2 and Th17) and natural killer T cell.</p>
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		<item>
		<title>CD47-related Signaling Pathways &#038; Research Progress on the Relationship with Related Diseases (Part One)</title>
		<link>https://www.creative-biolabs.com/blog/index.php/cd47-related-signaling-pathways-research-progress-on-the-relationship-with-related-diseases-part-one/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Mon, 12 Apr 2021 02:42:53 +0000</pubDate>
				<category><![CDATA[Biological Knowledge]]></category>
		<category><![CDATA[CD47]]></category>
		<category><![CDATA[Protein]]></category>
		<category><![CDATA[Protein Protein Interaction]]></category>
		<guid isPermaLink="false">http://www.creative-biolabs.com/blog/?p=1620</guid>

					<description><![CDATA[Cluster of differentiation 47 (CD47) is a widely expressed glycoprotein on the cell surface, which can interact with a variety of intracellular and extracellular proteins such as thrombospondin-1 (TSP-1) and signal regulatory<a class="moretag" href="https://www.creative-biolabs.com/blog/index.php/cd47-related-signaling-pathways-research-progress-on-the-relationship-with-related-diseases-part-one/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><a href="/target-cd47-584.htm"><span style="color: #0000ff;"><strong>Cluster of </strong></span><span style="color: #0000ff;"><strong>differentiation 47</strong></span></a> (CD47) is a widely expressed glycoprotein on the cell surface, which can interact with a variety of intracellular and extracellular proteins such as thrombospondin-1 (TSP-1) and signal regulatory protein α (SIRPα) and participate in the regulation of various signaling pathways that play an important role in the occurrence and development of many diseases such as tumors, cardiovascular diseases, and autoimmune diseases. The understanding of the CD47 structure, expression, interaction with other proteins, related signaling pathways, and the relationship with diseases, can help the development of therapeutic strategies targeting CD47.</p>
<p>Previous studies showe that CD47 interacts with integrins αvβ3, αⅡ, bβ3, and α2β1 to regulate integrin function and cell response to extracellular matrix proteins containing arginine-glycine-aspartic acid (RGD). Therefore, it is called integrin-related protein. CD47 is highly expressed in a variety of tumors, such as ovarian cancer, leukemia, breast cancer, colon cancer, bladder cancer, glioblastoma, hepatocellular carcinoma, and prostate tumor. Studies also indicate that anti-CD47 antibodies can stimulate macrophages to clear tumor cells, so CD47 has become a research hotspot in recent years.</p>
<p><strong>1 Structure, Expression, and Interaction of CD47</strong></p>
<p><strong>1.1 Structure</strong></p>
<p>CD47 belongs to the immunoglobulin superfamily, which has two isomers, one containing N glycosylation and the other containing glycosaminoglycan modifications at its 64 and 79 serines. The CD47 structure consists of three domains, the N-terminal extracellular immunoglobulin variable (IgV) domain, the highly hydrophobic five-transmembrane domain, and the short variable C-terminal intracellular domain, as shown in figure 1.</p>
<p style="text-align: center;"><a href="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/Schematic-diagram-of-CD47-structure.png"><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-1621" src="http://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/Schematic-diagram-of-CD47-structure.png" alt="" width="317" height="310" srcset="https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/Schematic-diagram-of-CD47-structure.png 317w, https://www.creative-biolabs.com/blog/wp-content/uploads/2021/04/Schematic-diagram-of-CD47-structure-300x293.png 300w" sizes="(max-width: 317px) 100vw, 317px" /></a></p>
<p style="text-align: center;">Fig. 1. Schematic diagram of CD47 structure. (<em>TRENDS in Cell Biology</em>)</p>
<p>CD47 interacts with its ligands TSP1 and SIRPα through the extracellular IgV domain. The IgV domain is modified by N-linked glycosylation and O-linked glycosylation, which is necessary for the interaction between CD47 and TSP. There is a long disulfide bond between the amino acid residue Cys33 on the IgV domain and the amino acid residue Cys263 on the last extracellular loop of the transmembrane domain, which is necessary for the binding of CD47 ligands, signal transduction, and localization to the lipid raft. There are four types of alternative splicing of the intracellular domain. According to the difference in gene structure and peptide sequence, it can be divided into type Ⅰ, type Ⅱ, type Ⅲ, and type Ⅳ. The number of amino acids varies from 3 to 36. At present, type Ⅱ is the most important and most expressed splice form, followed by type Ⅳ, which is mainly expressed in the brain and peripheral nervous system, while type I is only significantly expressed in keratinocytes, and type Ⅲ is mainly related to memory consolidation.</p>
<p><strong>1.2 Expression</strong></p>
<p>CD47 is expressed on the surface of almost all cells, including red blood cells and platelets, and its expression level varies according to the immune or pathological status of the body. CD47 is highly expressed various tumors, and the phagocytosis of tumors can be enhanced by blocking CD47. Xu <em>et al</em>. found that anti-CD47 therapy can increase the phagocytic function of macrophages, reduce tumor weight, and inhibit spontaneous metastasis in osteosarcoma xenotransplantation model. Zhang <em>et al</em>. found that blocking CD47 can enhance the phagocytosis of macrophages to tumor cells, reduce tumor load, and improve the survival rate of patients with glioblastoma. Similarly, Yoshida <em>et al</em>. found that blocking CD47 can enhance the phagocytosis of macrophages in gastric cancer cells.</p>
<p>All these suggest that CD47 may be an important survival signal molecule of tumor cells and is closely related to the occurrence and development of tumor. In the process of immune response, the expression of CD47 on the surface of CD4 effector T cells is increased, which prevents memory T cells from being cleared by macrophages and prolonging their life cycle. Similarly, the high expression of CD47 on the surface of hematopoietic stem cells (HSCs) also protected it from macrophage phagocytosis. When the expression of CD47 on the surface of CD34+ CD38- HSCs is selectively down-regulated, hemophagocytic lymphohistiocytosis (HLH) may occur.</p>
<p><strong>1.3 Interaction</strong></p>
<p>CD47 mainly interacts with three extracellular ligands through the extracellular IgV domain, which are CD47-TSP1, CD47-SIRP α, and CD47-CD47, respectively. Due to the small intracellular domain of CD47, only a limited number of intracellular signaling proteins interact with CD47, mainly BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and protein-linking integrin-associated protein and cytoskeleton (PLIC). The <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/biomolecular-interaction-analysis-services.html">transverse interaction</a></span></strong> between CD47 and other transmembrane proteins may play an important role in the signal transduction pathway of CD47, such as integrin αvβ3, vascular endothelial growth factor receptor 2 (VEGFR2), Rh blood group antigen complex, CD47, factor associated suicide (Fas), and CD14.</p>
<p>1.3.1 Extracellular Interaction</p>
<p>The first found endogenous ligand of CD47 was TSP1, a member of the TSP family, including TSP1~TSP5. TSP1 is a transient expression cell matrix protein, which in different environments, regulates cell function by combining with cell surface receptors or other extracellular matrix components. TSP1 has a large structure and contains multiple domains, which enable it to interact with various cell surface receptors and extracellular matrix, including integrins (mainly β1 and β3), CD47, CD36, heparan sulfate proteoglycan (HSPG), low density lipoprotein receptor-related protein 1 (LRP1), and very low-density lipoprotein (VLDL) receptor. TSP1 binds to CD47 through the VVM sequence on its C-terminal binding domain, and then affects a variety of cell functions, such as cell migration and adhesion, cell proliferation and apoptosis, and regulation of angiogenesis and inflammation.</p>
<p>The second found endogenous ligand was SIRPα. SIRP α, which belongs to the immunoglobulin superfamily, is a transmembrane protein that can be expressed at different levels on the surface of myeloid cells. The expression of SIRPα on the surface of phagocytes seems to be very stable and will not be affected by the degree of inflammation, while the expression of CD47 changes with different immune status or diseases. The extracellular N-terminal of SIRPα contains three Ig-like domains and its cytoplasmic C-terminal contains two immunoreceptor tyrosine-based inhibitory motif (ITIM). ITIM mediates the recruitment and activation of SHP-1 and SHP-2, which affects the intracellular signal transduction pathway. SIRPα binds to the IgV domain of CD47 through its IgV domain of N-terminal, and the interaction between them plays a role in controlling cell phagocytosis and can produce a signal of &#8220;don&#8217;t eat me&#8221;.</p>
<p>Adhesion between cells requires the presence of CD47 but not its ligand, which indicates that the IgV domains of CD47 on the two cells also has homotypic binding. However, there is insufficient evidence that the interaction between CD47s can produce signal transduction.</p>
<p>1.3.2 Membrane Surface Interaction</p>
<p>CD47 interacts with integrin αvβ3 and other integrin subtypes, such as αⅡbβ3, α2β1, αLβ2, and α4β1. CD47 triggers subsequent intracellular signal transduction by activating integrin, which is independent of its transmembrane domain. CD47 binds to these integrins and can change the signal targets of integrins, such as focal adhesion kinase and paxillin. The CD47-integrin complex is also associated with trimeric G-protein and participates in the regulation of cAMP signal transduction.</p>
<p>CD47 can interact with VEGF and VEGFR2, while TSP1 can suppress the downstream signal cascade of VEGF through CD47. In addition, co-immunoprecipitation and fluorescence resonance energy transfer showed that CD47 could interact with VEGFR2 directly, but this interaction would be destroyed by the binding of TSP1 and CD47 and the binding of VEGF to VEGFR2, thus inhibiting the signal transduction of VEGFR2.</p>
<p>1.3.3 Intracellular Interaction</p>
<p>Using CD47 transmembrane domain and C-terminal tail as bait for <span style="color: #0000ff;"><strong><a style="color: #0000ff;" href="/yeast-two-hybrid-y2h-service.html">yeast two-hybrid</a></strong></span> system, BNIP3 was found to be a cytoplasmic binding ligand from human lymphocyte cDNA library. Reverse inhibition of BNIP3 can inhibit CD47-mediated apoptosis. Activation of CD47 with TSP1 can induce BNIP3 transfer to mitochondria, resulting in cell death. However, the combination of SIRPα and CD47 could not cause BNIP3 metastasis.</p>
<p>Using the integrin-related protein-2 (IAP2) and IAP4 splicing isoforms of the CD47 cytoplasmic tail as bait for the yeast two-hybrid system, two other ubiquitin-related proteins were identified as CD47 cytoplasmic binding ligands, which are integrin-related proteins and cytoskeleton proteins PLIC1 and PLIC2, respectively. Follow-up studies found that PLIC1 binds to G-protein βγ subunit (Gβγ), which makes CD47 bind to trimeric G protein and regulate its downstream signal pathway.</p>
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