Antibody News

SREBP2 - regulating cholesterol homeostasis and lipid metabolism

Wednesday, July 1, 2015 - 14:47

Sterol regulatory element-binding proteins (SREBP) are important transcription factors regulating the synthesis and uptake of lipids including cholesterol. This essential role in lipid metabolism makes investigations into the functions SREBPs important for understanding metabolic disorders such as diabetes and may provide insight for future drug treatment strategies. SREBPs are basic helix-loop-helix (bHLH) leucine zipper transcription factors that bind to sterol response elements (SRE) to enhance the expression of target genes including LDL receptor and lipid synthesis genes. In humans there are two SREBP genes, SREBP1 and SREBP2. SREBP1 is expressed primarily in the liver while SREBP2 is ubiquitously expressed. SREBPs are synthesized as ER membrane proteins where they bind with SREBP cleavage-activating protein (SCAP), an important cholesterol sensor and transporter. This association with SCAP retains SREBP in...

MMP3 - a potential target for arthritis therapies

Monday, June 29, 2015 - 14:04

Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix proteins. MMPs are essential for tissue remodeling during normal processes such as embryonic development as well as pathological conditions such as arthritis and tumor metastasis. MMP3, a member of the stromelysin family, has broad specificity for proteins such as collagens, fibronectin, proteoglycans, and elastin making it an important player in extracellular matrix remodeling. These activities are especially important during tumorigenesis by enhancing epithelial to mesenchymal transition. MMPs are generally secreted as a proform and subsequently processed and cleaved into the active form. However under oxidative stress and during apoptotic signaling MMP3 can also be found in its active form inside of cells and may have important implications in neurodegenerative diseases like Alzheimer disease and Parkinson disease (1). A number of specific MMP inhibitors are currently in...

FGFR1 - regulating cell growth and proliferation in development and disease

Friday, June 26, 2015 - 13:15

The vertebrate fibroblast growth factor receptor (FGFR) family is an important group of proteins involved in embryonic development and the growth and proliferation of adult cells. Mutations in FGFR proteins can lead to pathologies including bone or limb defects and various forms of cancer. FGFR proteins are receptor tyrosine kinases that, upon ligand binding, dimerize and signal through the MAPK and PLCγ pathways. FGFR1 is a well characterized member of this protein family consisting of an extracellular region, a single-pass transmembrane domain, and the intracellular tyrosine kinase domain. The extracellular region contains a heparin binding domain responsible for interaction with the extracellular matrix while the intracellular domain interacts with downstream effectors after receptor dimerization to propagate signals (1). FGFR1 exists in many alternatively spliced isoforms including a soluble, secreted isoform lacking the transmembrane and kinase domains. While...

Calnexin - an ER chaperone that folds the cell's glycoproteins

Thursday, June 18, 2015 - 14:49

Calnexin is an abundant 90kDa chaperone protein that resides in the membrane of the endoplasmic reticulum. Calnexin and the related calreticulin protein function together to ensure the proper folding of glycoproteins. By binding to partially folded or misfolded proteins, Calnexin functions as an important quality control monitor ensuring proper folding of proteins destined for the plasma membrane or secretion. Calnexin contains a lectin site that recognizes substrate proteins through a transient and intermediate oligosaccharide containing a terminal glucose residue. Through this interaction calnexin binds to and participates in the folding of most if not all glycoproteins. Calnexin also contains binding sites for it cofactors ATP and Ca2+  and is able to recruit enzymes that catalyze disulfide bond formation and isomeriztion to aid in folding. Calnexin binding retains substrate proteins in the ER until they are fully mature and their...

GPR78 - an orphan receptor involved in psychiatric illness

Monday, June 15, 2015 - 15:06

G-protein coupled receptor 78 (GPR78) was identified based on homology to other GPCR family members. The GPR78 gene encodes an orphan receptor protein that is 363 amino acids in length and contains the typical seven transmembrane domain found in GPCRs. The protein is widely expressed in the mammalian brain including the pituitary and is also found in the placenta. While a ligand for GPR78 has yet to be identified, its expression pattern suggests a potential role in hormone and stress regulation as well as during pregnancy. Future research with GPR78 antibodies may assist in assays to identify the endogenous and pharmaceutical ligands for this orphan receptor. A study of GPR78 in a tissue culture system demonstrated constitutive activity as well as elevated cAMP levels providing preliminary evidence of GPR78’s function in signal transduction (1). Further investigation using GPR78 antibodies...

Integrin alpha v beta 3 - a target for inhibiting tumor angiogenesis

Friday, June 12, 2015 - 14:37

Integrins are a family of transmembrane proteins involved in diverse processes including cell adhesion, signal transduction, cell migration, and differentiation. They exist as heterodimers consisting of noncovalently linked alpha and beta subunits. Integrin complexes span the plasma membrane and link the cytoskeleton with the extracellular matrix. In mammals there are 18 alpha and 8 beta subunits that can assemble into 24 distinct integrin heterodimers with alternative splicing adding even more diversity. In addition to binding the extracellular matrix, integrins also bind to endogenous ligands including soluble proteins and cell surface proteins. Integrin alpha v beta 3 (Integrin αvβ3), also known as the vitronectin receptor, has important roles in angiogenesis and tumor metastasis and binds to a wide range of extracellular matrix proteins containing the RGD-motif. Integrin alpha v beta 3 is highly expressed in cells of the bone, placenta, and invasive tumors where it...

LAMP2 - a marker of lysosomes and late endosomes

Thursday, June 11, 2015 - 14:42

Lysosomes are membrane-bound organelles responsible for the degradation of various biological macromolecules. Vesicles containing hydrolytic enzymes bud from the Golgi and fuse with endosomes to form the mature lysosome capable of breaking down various types of cargo. Their general function in recycling biological molecules places lysosomes at center of various processes including autophagy, endyocytosis, and phagocytosis. These functions are essential for maintaining cellular homeostasis through, for example, autophagy of damaged organelles or the endocytosis and degradation of activated signaling receptor complexes. Lysosomal-associated membrane protein-2 (LAMP-2) is ubiquitously expressed and is an abundant component of the lysosomal membrane. LAMP-2 contains a large luminal domain that is heavily glycosylated followed by a single transmembrane domain and a small cytoplasmic facing carboxyl terminus. LAMP-2 acts as a receptor for the degradation of specific...

TGF-beta 1 - a versatile signaling molecule with roles in development and disease

Wednesday, June 10, 2015 - 14:52

The transforming growth factor-β (TGF-beta) family consists of a wide variety of signaling proteins with roles in development. TGF-beta signaling controls growth, differentiation, and immune responses and is often misregulated in cancer. TGF-beta 1 is the most widely expressed and abundant isoform of the TGF-beta family. TGF-beta proteins signal through two classes of receptors: type I (TβRI) and type II (TβRI). These receptor proteins are serine threonine kinases found at the cell surface. Binding of TGF-beta induces the formation of a heterocomplex with TβRI and TβRII and leads to the phosphorylation of TβRI by TβRII. The active phosphorylated form of TβRI recruits and phosphorylates downstream effector SMAD proteins, which can then translocate to the nucleus where they can regulate transcription. Non-canonical signaling by TGF-beta 1 can also be mediated through various pathways including MAPKs, small GTPases, and PI3Ks. TGF-beta proteins are synthesized as pro-...

PINK1 - performing mitochondrial quality control and protecting against Parkinson’s disease

Monday, June 8, 2015 - 15:39

PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinase with important functions in mitochondrial quality control. Together with the Parkin protein, PINK1 is able to regulate the selective degradation of damaged mitochondria through autophagy. Normally PINK1 is imported into the mitochondria where it is targeted for proteolytic cleavage. This cleavage event results in unstable products and is the reason PINK1 is difficult to detect in healthy mitochondria. In damaged mitochondria loss of the membrane potential prevents the import of PINK1 and causes it to reside in the outer mitochondrial membrane. Exposed PINK1 in the outer membrane then recruits Parkin which acts as an E3 ligase to ubiquitinate mitochondrial proteins. This leads to mitochondrial degradation through either proteasome or autophagy pathways and can protect cells from oxidative stress induced apoptosis.  PINK1 may also regulate mitochondrial fission/fusion events....

NOXA - a BH3-only protein balancing cell death decisions

Friday, June 5, 2015 - 15:30

Noxa is a BH3-only protein involved in regulating cell death decisions. Noxa is a primary p53-response gene and is upregulated in response to p53 overexpression or DNA damage. Noxa can also be induced by alternative mechanisms including through a hypoxia-response element found in its promoter. Noxa localizes to mitochondria where it binds to Mcl1, an anti-apoptotic Bcl2 family member. Binding of Mcl1 by Noxa not only neutralizes its pro-survival effects but can also lead to proteasomal degradation of Mcl1 to further enhance apoptosis. While Noxa is important for induction of cell death in some cellular contexts, overexpression of Noxa does not always lead to a strong apoptotic response. This suggests Noxa-induced cell death may depend on the levels of other Bcl2-like and BH3-only proteins within the cell. While the relevance of Noxa in tumor suppression is unclear insight into the regulation of...

IRE1 - an important sensor in the unfolded protein response pathway

Thursday, June 4, 2015 - 15:18

During cellular stress the protein folding capacity of the ER is diminished. In order to maintain homeostasis and ensure proper protein folding cells activate the unfolded protein response (UPR), a signaling network consisting of sensors and effectors to enhance the chaperone activity of the cell, increase degradation of accumulated proteins, and/or trigger apoptosis.  Inositol-requiring enzyme 1 (IRE1), an ER-transmembrane protein, is an essential component of the UPR pathway important for sensing and responding to ER stress. IRE1 contains an ER luminal stress-sensing domain and a cytoplasmic facing RNase domain. Upon activation by the presence of misfolded substrates IRE1 proteins oligomerize and activate their RNase activity. The main function of IRE1’s RNase activity is the unconventional splicing of the transcription factor XBP1 mRNA. Splicing of XBP1 allows for the translation of functional transcription factor and the upregulation...

ATG5 - an essential regulator of autophagosome assembly

Wednesday, June 3, 2015 - 15:02

Autophagy is important for the removal of damaged organelles or proteins as well as for the regulation of cellular homeostasis in response to stress. Proteins or organelles that are targeted for degradation are engulfed in a double-membrane structure called the autophagosome that eventually fuses with the lysosome to mediate cargo degradation. Atg5 plays an important regulatory role in the early steps of this process. During early autophagosome assembly Atg5 is conjugated to Atg12, an ubiquitin-like protein, and associates with Atg16. This complex of Atg5-Atg12/Atg16 forms a large multimeric complex and localizes to early autophagsome structure where it plays an essential role in the lipidation of Atg8. Atg8 is another ubiquitin-like protein that, upon lipidation, inserts into the autophagosome membrane to help recruit additional lipid components and autophagy machinery as well as cargo targeted for degradation. The...

ATF6 - monitoring and regulating protein folding under cellular stress

Monday, June 1, 2015 - 14:54

During times of cellular stress overloading of the protein folding machinery leads to the accumulation of incorrectly folded proteins. This triggers the unfolded protein response (UPR) in order to try to reestablish homeostasis or, if this fails, to induce apoptosis. The UPR pathway is mediated by a group of ER-associated transmembrane receptors including activating transcription factor 6 (ATF6). The presence of misfolded proteins is monitored by BiP, an Hsp70 family member. BiP functions as a chaperone protein and sensor by recognizing and binding to exposed hydrophobic stretches in unfolded proteins. Normally BiP is associated with membrane-bound ATF6 and retains it in the ER. Under cellular stress BiP disassociates and preferentially binds to misfolded proteins allowing ATF6 translocation to the Golgi. Once at the Golgi ATF6 is cleaved releasing a 50kD soluble transcriptional domain that translocates to the nucleus to regulate gene expression in order to increase...

CD163 - a scavenger receptor with important roles in inflammation

Friday, May 29, 2015 - 14:46

Scavenger receptors play important roles in homeostasis and innate immunity by binding to endogenous and foreign molecules. Scavenger receptors on the plasma membrane of macrophages bind to ligand and allow their internalization and can also mediate pro- or anti-inflammatory signaling. The plasma membrane glycoprotein CD163 is a member of the scavenger receptor cysteine-rich (SRCR) protein family. CD163 contains nine SRCR domains and is expressed in macrophages and monocytes where it plays a role in innate immunity and regulation of inflammation in response to ligand binding. CD163 binds specifically to hemoglobin (Hb)-haptoglobin (Hp) complexes produced during hemolysis to allow their internalization and lysosomal degradation. Additionally, CD163 has been shown to bind other ligands including some bacterial or viral pathogens. Recognition of these ligands leads to internalization and breakdown as well as...

ATG7 - an E1 enzyme for the ubiquitin-like autophagy proteins

Friday, May 15, 2015 - 09:47

Autophagy is an essential cellular process that maintains homeostasis through the degradation and recycling of cytoplasmic organelles and macromolecules. Substrates targeted for autophagy are engulfed in a double-membrane structure called the autophagosome which is then targeted to the lysosome for degradation. The initiation of autophagy requires two separate ubiquitin-like protein (UBL) systems that regulate autophagosome assembly. In these systems Atg7 acts as an E1-like enzyme for the UBLs Atg12 and Atg8. Atg7 binds to and activates these UBLs to allow their transfer to an E2 enzyme and eventually their targets. Upon initiation of autophagosome assembly Atg7 binds to the UBL Atg12 and transfers it to its final binding partner Atg5 via the E2 enzyme Atg10. The Atg12-Atg5 conjugate assembles into a large multimeric complex along with Atg16....

p62/SQSTM1 - targeting ubiquitinated proteins for autophagic degradation

Friday, May 15, 2015 - 08:29

During autophagy ubiquitinated cargo or substrates are engulfed in a double-membrane autophagosome and transported to the lysosome for degradation. This process is important for maintaining cellular homeostasis and for degrading damaged organelles or misfolded protein aggregates. p62, also known as sequestosome 1 (SQSTM1), is an autophagy receptor that recognizes and recruits cargo to the autophagosome through its interaction with Atg8. Atg8, known as LC3 in mammals, is a ubiquitin-like protein that is conjugated to the lipid phosphatidylethanolamine which anchors it into the double-membrane phagopore structure. Atg8/LC3 is essential for binding to and recruiting the core autophagy machinery through an Atg8 interacting motif (AIM) or through the LC3-Interacting region (LIR). AIM/LIR containing autophagy receptors, including p62/SQSTM1, recognize ubiquitinated proteins and target them to the autophagosome for destruction. Autophagy is...

Hsc70 - a chaperone protein with diverse cellular functions

Friday, May 15, 2015 - 08:21

Heat shock cognate 71 kDa protein (Hsc70), also known as HSPA8, is a member of the heat shock protein 70 family (Hsp70). Unlike Hsp70, it is a constitutively expressed chaperone protein and is involved in diverse cellular processes including protein folding and protein degradation. Hsc70 consists of two domains: the nucleotide binding domain (NBD) and the substrate binding domain (SBD). Hsc70, with the help of accessory proteins, exerts its chaperone activity by binding to short hydrophobic stretches of nascent or unfolded polypeptides through the SBD in an ATP-dependent manner. ATP hydrolysis then triggers a conformational change to induce protein folding and the release of the substrate. Nucleotide exchange factors then facilitate the exchange of ADP for ATP allowing Hsc70 to bind to a new substrate and repeat the cycle. The ATPase activity of Hsc70 is also important for endocytosis during the uncoating of clathrin-coated vesicles. In conjunction with cochaperones...

HLA G - mediating immune tolerance during pregnancy

Friday, May 15, 2015 - 08:11

Human leukocyte antigen G (HLA G) is a major histocompatibility complex (MHC) class I molecule that is primarily expressed in the placenta and is essential for the immune tolerance of the fetus during pregnancy. Unlike many HLA genes, HLA G has relatively few variants and is alternatively spliced into seven different isoforms. Of these isoforms four are membrane-bound while three are predicted to be soluble. Both the membrane-bound and soluble form of HLA G can induce immune tolerance by binding to inhibitory receptors on various immune cells including macrophages and monocytes. HLA G is aberrantly expressed in diseases such as multiple sclerosis, viral infection, and cancer. In cancer HLA G is thought to function as an important mechanism to escape the immune system. Elevated HLA G is found in cancer patient serum and may serve as an important diagnostic tool to distinguish between malignant and benign tumors as well as sensitivity to chemotherapeutic agents.
 ...

ATG12 - a ubiquitin-like protein essential for autophagosome assembly

Friday, May 15, 2015 - 07:58

Atg12 is a ubiquitin-like protein that plays an essential role in cellular homeostasis by regulating the degradation and recycling of cytoplasmic organelles and macromolecules. Atg12 is one of two ubiquitin-like protein systems that is required during the early steps of autophagosome formation. Upon the initiation of phagopore assembly Atg12 is activated by binding to the E1-like enzyme Atg7 and is then transferred to the E2 enzyme Atg10. Finally, Atg12 is conjugated to a lysine residue in Atg5 allowing the formation of a large multimeric complex with Atg16. This Atg12-Atg5-Atg16 complex localizes to the surface of the expanding phagopore where it functions as an E3 ligase for the lipidation of Atg8, the other autophagy-specific ubiquitin-like protein. Atg8, or LC3 in mammals, is conjugated to the lipid phosphatidylethanolamine and is...

CD74 - a central player in antigen presentation by MHC class II

Thursday, May 14, 2015 - 15:16

Cluster of differentiation 74 (CD74) is an important integral membrane protein that serves as a chaperone for MHC class II molecules. CD74, also known as the invariant chain or Ii, is needed for the proper folding and trafficking of MHC class II in antigen presenting cells. CD74 serves as a scaffold for MHC class II assembly. During assembly CD74 blocks the peptide binding cleft of MHC class II to prevent binding of antigenic peptides. Following endocytosis of antigen the CD74-MHC class II complex is trafficked to the endosome where CD74 is digested leaving only the 9 amino acid CLIP peptide in the binding cleft. CLIP peptide can then be released to allow the binding of antigenic peptide and the trafficking of the antigen bound MHC molecules to the plasma membrane. CD74 also plays important roles in various cell signaling pathways including the activation of nuclear factor-kB during B-cell maturation. CD74's function in B-cell...

Mucin 1 - a mucosal epithelial glycoprotein with importance in cancer diagnostics

Thursday, May 14, 2015 - 15:08

Mucin 1 (Muc1) is a heavily glycosylated protein that coats mucosal epithelial cells of the lungs, intestines, and other organs. Muc1 is thought to protect cells by binding to pathogens and responding to infections. During trafficking to the plasma membrane Muc1 is proteolytically cleaved in the endoplasmic reticulum to form a stable heterodimeric complex of two fragments. The smaller C-terminal region contains the cytoplasmic tail and transmembrane domain and is non-covalently bound to the larger glycosylated extracellular domain. Further cleavage or processing of the extracellular domain can cause release or shedding into the extracellular space and is thought to be involved in protein turnover and degradation or could potentially trigger a signaling response in the cytoplasmic domain. Muc1 is highly overexpressed in breast, ovarian, and prostate cancers and is correlated with metastasis and poor survival. Overexpressed Muc1 localizes throughout the cell in these...

Integrin Beta 1/CD29 - a cell adhesion and cell signaling protein with diverse functions

Thursday, May 14, 2015 - 13:42

Integrins are a large family of trasmembrane proteins involved in cell adhesion and form a link between the intracellular cyskeletal proteins and extracellular matrix proteins. Integrins exist as heterodimers consisting of alpha and beta subunits. In addition to cell adhesion these integrin complexes play key roles in diverse processes such as signal transduction, cell migration, proliferation, differentiation, and apoptosis. Integrins consist of three domains: the extracellular domain, the transmembrane domain, and the cytoplasmic tail. The large globular extracellular domain is responsible for ligand binding while the transmembrane region is a single-pass α-helix. The cytoplasmic tails are short unstructured regions that form salt bridges between alpha and beta proteins as well as interact with adaptor proteins that link to the cytoskeleton. Integrin complexes are able to signal bidirectionally. Ligand binding on the outside of the cell can trigger an intracellular...

hnRNP A1 - a ribonucleoprotein regulating gene expression at many levels

Wednesday, May 13, 2015 - 14:42

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an abundant ubiquitously expressed protein with important roles in the regulation of gene expression. hnRNP A1 is involved in transcription as well as the splicing, trafficking, and translation of RNA transcripts. hnRNP A1 binds RNA targets in a sequence specific manner through two N-terminal RNA recognition motifs (RRM) and a C-terminal RGG box RNA binding domain. During transcription hnRNPA1 binds to the promoter of target genes and has been shown to function as both a transcriptional activator and repressor. During the removal of introns hnRNP A1 is present in various splicing complexes and interacts with the essential splicing factor U2AF. hnRNP A1 also contributes to alternative splicing by modulating splice site selection. Once in the cytoplasm hnRNPA1 associates with internal ribosomal entry sites (IRES) of mature mRNA and can both inhibitor enhance translation depending on the...

Hsp90A - helping to fold a wide variety of signal transduction proteins

Monday, May 11, 2015 - 14:49

Heat-shock protein 90 (Hsp90) is a conserved ATP-dependent chaperone with diverse cellular functions. Hsp90 is ubiquitously expressed but is further induced upon cellular stress such as heat-shock or nutrient deprivation. Hsp90 is essential for the proper folding of a diverse set of proteins called clients. These client proteins consist of important signal transduction proteins including transcription factors, kinases, and steroid hormone receptors. By regulating the final folding steps of these client proteins Hsp90 plays an important role in many cellular signaling pathways. Hsp90 exists in two closely related isoforms; Hsp90A localizes to the cytosol while Hsp90B localizes to the endoplasmic reticulum. Hsp90A exists as a member of a protein complex and is associated with various co-chaperone proteins that mediate substrate recruitment. While the mechanism of protein folding is unclear an Hsp90A dimer is thought to bind to partially...

Bcl-2 - an antiapoptotic protein with an important role in cancer cell survival

Thursday, May 7, 2015 - 14:31

B-cell lymphoma 2 (Bcl-2) protein is an oncogene that normally acts as an apoptotic inhibitor and localizes to the mitochondrial membrane where it prevents the release of cytochrome c. The Bcl-2 protein family consists of over 20 proteins each containing at least one Bcl-2 homology (BH) domains and have either proapoptic or antiapoptotic activities. During induction of apoptosis the oligomerization of the Bcl-2 family proteins Bax and Bak forms a pore in the mitochondrial membrane triggering the release of cytochrome c. While it is still unclear, Bcl-2 is thought to directly bind and sequester BH-3 domain proapoptotic proteins such as BIM or BID. Upon release, BIM or BID are free to bind and activate Bax/Bak to induce cell death. Bcl-2 is often overexpressed in tumor cells where it can enhance cell survival despite the presence of apoptotic...

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