Apoptosis adaptor proteins are critical components in the signaling pathways that regulate programmed cell death, functioning as key intermediaries that facilitate the transmission of apoptotic signals from receptors on the cell surface to the effector mechanisms within the cell. These proteins play essential roles in both the intrinsic and extrinsic apoptosis pathways, ensuring that signals are accurately relayed to initiate the cascade of events leading to cell death.
In the context of the extrinsic pathway, one of the most well-known apoptosis adaptor proteins is Fas-associated death domain (FADD). FADD is pivotal in mediating the signal transduction from death receptors such as Fas (CD95) and the TNF-receptor. Upon activation by their respective ligands, these receptors recruit FADD through homotypic death domain (DD) interactions. FADD then serves as a platform for the subsequent recruitment and activation of procaspase-8 through its death effector domain (DED), forming the death-inducing signaling complex (DISC). This complex initiates the caspase cascade, leading to apoptosis. Another important adaptor in this pathway is the TNF receptor-associated death domain (TRADD), which plays a key role in TNF receptor signaling, facilitating both apoptotic and survival pathways.
In the intrinsic pathway, the apoptosome plays a central role as an adaptor complex. The apoptosome is formed when cytochrome c released from mitochondria in response to pro-apoptotic signals binds to the apoptotic protease activating factor-1 (Apaf-1) in the presence of dATP. This binding leads to Apaf-1 oligomerization into the apoptosome, which then recruits and activates procaspase-9. The activated caspase-9 cleaves and activates downstream effector caspases, such as caspase-3, completing the execution phase of apoptosis.
These apoptosis adaptor proteins not only facilitate the recruitment and activation of caspases but also integrate signals from various upstream pathways, including those mediated by cellular stress, DNA damage, and survival signals. By serving as crucial nodes within the complex web of apoptotic signaling, these adaptor proteins ensure the fidelity and specificity of the apoptotic response. Dysfunction in the regulation or expression of these proteins can lead to pathological conditions where cells either undergo excessive apoptosis or evade apoptosis improperly, as seen in many cancer types.
Figure 1 Mechanism of apoptosis and alteration of its pathways in cancer. (Goldar, 2015)
CALD1, or Caldesmon, is a multifunctional actin-binding protein that plays a critical role in the regulation of smooth muscle contraction and cytoskeleton organization in non-muscle cells. Caldesmon exists in two isoforms: a high-molecular-weight isoform (h-Caldesmon), which is predominantly expressed in smooth muscle cells, and a low-molecular-weight isoform (l-Caldesmon), found in non-muscle cells. The protein modulates the interaction between actin and myosin, the central players in muscle contraction, by binding to both and inhibiting the ATPase activity of myosin in a calcium/calmodulin-dependent manner. In smooth muscle cells, h-Caldesmon is a key component in the contractile apparatus, where it helps regulate muscle tension and relaxation by modulating the actomyosin interactions in response to intracellular calcium levels. Its function is vital for normal vascular tone and motility in other smooth muscle-containing organs, such as the intestines and uterus. In non-muscle cells, l-Caldesmon contributes to the stabilization of the actin cytoskeleton, impacting cell shape, motility, and division. By influencing the dynamics of the cytoskeleton, Caldesmon plays a role in cellular processes that require cytoskeletal rearrangement, including cell adhesion, migration, and proliferation. Dysregulation of CALD1 has been implicated in various pathological conditions, including vascular diseases, where altered smooth muscle contraction can contribute to hypertension and other vascular dysfunctions. In cancer, changes in Caldesmon expression have been associated with tumor progression and metastasis, likely due to its effects on cell motility and the invasive properties of cancer cells.
FADD, or Fas-Associated protein with Death Domain, is a pivotal adaptor molecule in apoptosis and cell signaling pathways. It plays a crucial role in the extrinsic pathway of apoptosis, particularly in mediating the apoptotic signals triggered by death receptors, including Fas (CD95), TNF receptor, and TRAIL receptors. Upon activation by these receptors, FADD is recruited to the death-inducing signaling complex (DISC), where it interacts through its death domain (DD) with the death domains of these receptors. FADD also contains a death effector domain (DED), which enables it to recruit and bind other DED-containing proteins like pro-caspase-8 and pro-caspase-10. This interaction is critical for the initiation of a cascade of downstream signaling events leading to caspase activation, culminating in the execution phase of apoptosis, where cellular components are systematically dismantled. The function of FADD is not limited to apoptosis; it is also implicated in regulating cell cycle progression and proliferation. Dysregulation of FADD and its associated pathways can lead to various pathological conditions, including cancer. Overexpression or malfunction of FADD has been linked to the evasion of apoptosis, contributing to the survival and proliferation of cancer cells. Conversely, defects in FADD-mediated signaling can lead to immune deficiencies and developmental issues due to impaired apoptosis. Strategies that modulate FADD function or enhance its interaction with death receptors are being explored to trigger apoptosis in cancer cells selectively. Additionally, because of its role in immune cell regulation, FADD is also studied in the context of autoimmune diseases and inflammatory responses.
YWHAZ, commonly known as 14-3-3 zeta, is a member of the 14-3-3 family of proteins, which are highly conserved and ubiquitously expressed across eukaryotic organisms. These proteins are key regulatory molecules that interact with a wide array of signaling proteins involved in various cellular processes including the cell cycle, apoptosis, and signal transduction pathways. YWHAZ specifically binds to phosphoserine-containing proteins, playing a critical role in mediating signal transduction cascades and influencing cellular localization and activity of target proteins. The ability of YWHAZ to modulate the function of a multitude of signaling proteins positions it as an integral player in cellular homeostasis. It is involved in critical regulatory processes such as inhibiting apoptosis by binding to and sequestering pro-apoptotic proteins like BAD and BAX away from mitochondria. Additionally, YWHAZ plays a role in cell cycle control by interacting with cyclins and checkpoint kinases, modulating the progression and timing of the cell cycle. The importance of YWHAZ extends into various clinical implications. Its overexpression has been observed in several types of cancers, where it is thought to contribute to tumor progression by enhancing survival signaling and promoting resistance to apoptosis. This has made YWHAZ a potential biomarker and target for therapeutic intervention in cancer treatment. Furthermore, alterations in the expression and function of YWHAZ have been linked to neurological disorders, suggesting its role in neuronal signaling and brain function.
Biomarker | Alternative Names | Gene ID | UniProt ID | Roles |
BCAP31 | B Cell Receptor Associated Protein 31; C6-AG Tumor-Associated Antigen; DXS1357E; BAP31; B-Cell Receptor-Associated Protein 31; B-Cell Receptor Associated Protein 31; BCR-Associated Protein Bap31; BCR-Associated Protein 31; | 10134 | P51572 | This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16. |
CALD1 | Caldesmon 1; CDM; Testis Secretory Sperm-Binding Protein Li 227n; Caldesmon; H-CAD; L-CAD | 800 | Q05682 | CALD1 (Caldesmon 1) is a Protein Coding gene. Diseases associated with CALD1 include Mixed Endometrial Stromal And Smooth Muscle Tumor and Kidney Leiomyosarcoma. Among its related pathways are Cardiac conduction and Smooth Muscle Contraction. Gene Ontology (GO) annotations related to this gene include actin binding and myosin binding. |
CIDEA | CIDEA; Human CIDEA; CIDE-A | 1149 | O60543 | This gene encodes the homolog of the mouse protein Cidea that has been shown to activate apoptosis. This activation of apoptosis is inhibited by the DNA fragmentation factor DFF45 but not by caspase inhibitors. Mice that lack functional Cidea have higher metabolic rates, higher lipolysis in brown adipose tissue and higher core body temperatures when subjected to cold. These mice are also resistant to diet-induced obesity and diabetes. This suggests that in mice this gene product plays a role in thermogenesis and lipolysis. Alternatively spliced transcripts have been identified. |
CIDEC | CIDE3; FPLD5; FSP27; CIDE-3 | 63924 | Q96AQ7 | This gene encodes a member of the cell death-inducing DNA fragmentation factor-like effector family. |
CRADD | CASP2 And RIPK1 Domain Containing Adaptor With Death Domain; RIP-Associated ICH1/CED3-Homologous Protein With Death Domain; RIP-Associated Protein With A Death Domain; RAIDD; Caspase And RIP Adaptor With Death Domain; Caspase And RIP Adapter With Death Domain; Death Adaptor Molecule RAIDD; MRT34 | 8738 | P78560 | The protein encoded by this gene is a death domain (CARD/DD)-containing protein and has been shown to induce cell apoptosis. Through its CARD domain, this protein interacts with, and thus recruits, caspase 2/ICH1 to the cell death signal transduction complex that includes tumor necrosis factor receptor 1 (TNFR1A), RIPK1/RIP kinase, and numbers of other CARD domain-containing proteins. |
CRKL | CRK Like Proto-Oncogene, Adaptor Protein; V-Crk Avian Sarcoma Virus CT10 Oncogene Homolog-Like | 1399 | P46109 | CRKL (CRK Like Proto-Oncogene, Adaptor Protein) is a Protein Coding gene. Diseases associated with CRKL include Chromosome 22Q11.2 Deletion Syndrome, Distal and Leukemia, Chronic Myeloid. Among its related pathways are RET signaling and Chronic myeloid leukemia. Gene Ontology (GO) annotations related to this gene include SH3/SH2 adaptor activity. An important paralog of this gene is CRK. |
DFFA | DNA Fragmentation Factor Subunit Alpha; DNA Fragmentation Factor, 45kDa, Alpha Polypeptide; DNA Fragmentation Factor 45 KDa Subunit; Inhibitor Of CAD; DFF-45; DFF45 | 1676 | O00273 | Apoptosis is a cell death process that removes toxic and/or useless cells during mammalian development. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. |
FADD | Fas Associated Via Death Domain; Fas-Associating Death Domain-Containing Protein; Growth-Inhibiting Gene 3 Protein; Fas-Associating Protein With Death Domain; Fas (TNFRSF6)-Associated Via Death Domain; Mediator Of Receptor-Induced Toxicity | 8772 | Q13158 | The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals. Through its C-terminal death domain, this protein can be recruited by TNFRSF6/Fas-receptor, tumor necrosis factor receptor, TNFRSF25, and TNFSF10/TRAIL-receptor, and thus it participates in the death signaling initiated by these receptors. Interaction of this protein with the receptors unmasks the N-terminal effector domain of this protein, which allows it to recruit caspase-8, and thereby activate the cysteine protease cascade. Knockout studies in mice also suggest the importance of this protein in early T cell development. [provided by RefSeq, Jul 2008] |
MFGE8 | BA46; HMFG; MFGM; SED1; hP47; EDIL1; MFG-E8; SPAG10; OAcGD3S; HsT19888; lactadherin; O-acetyl disialoganglioside synthase breast epithelial antigen BA46 medin milk fat globule-EGF factor 8 protein sperm associated antigen 10 sperm surface protein hP47; Milk Fat Globule Protein | 4240 | Q08431 | This gene encodes a preproprotein that is proteolytically processed to form multiple protein products. The major encoded protein product, lactadherin, is a membrane glycoprotein that promotes phagocytosis of apoptotic cells. This protein has also been implicated in wound healing, autoimmune disease, and cancer. Lactadherin can be further processed to form a smaller cleavage product, medin, which comprises the major protein component of aortic medial amyloid (AMA). |
MYD88 | Myeloid Differentiation Primary Response 88; Myeloid Differentiation Primary Response Gene (88); Myeloid Differentiation Primary Response Protein MyD88; Mutant Myeloid Differentiation Primary Response 88; MYD88D | 4615 | Q99836 | This gene encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. These pathways regulate that activation of numerous proinflammatory genes. The encoded protein consists of an N-terminal death domain and a C-terminal Toll-interleukin1 receptor domain. Patients with defects in this gene have an increased susceptibility to pyogenic bacterial infections. Alternate splicing results in multiple transcript variants. |
PYCARD | ASC; TMS; TMS1; CARD5; TMS-1 | 29108 | Q9ULZ3 | This gene encodes an adaptor protein that is composed of two protein-protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the inflammatory and apoptotic signaling pathways via the activation of caspase. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ball-like aggregates near the nuclear periphery. Two transcript variants encoding different isoforms have been found for this gene. |
RIP1 | RIP1 | |||
RIPK1 | Receptor Interacting Serine/Threonine Kinase 1; Receptor (TNFRSF)-Interacting Serine-Threonine Kinase 1; Receptor-Interacting Protein Kinase 1; Serine/Threonine-Protein Kinase RIP; Receptor-Interacting Protein 1; Cell Death Protein RIP | 8737 | Q13546 | This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017] |
RIPK3 | Receptor Interacting Serine/Threonine Kinase 3; RIP-Like Protein Kinase 3; RIP-3; RIP3; Receptor-Interacting Serine/Threonine-Protein Kinase 3; Receptor-Interacting Serine-Threonine Kinase 3; Receptor Interacting Protein 3; Receptor-Interacting Protein 3; EC 2.7.11.1 | 11035 | Q9Y572 | The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, and contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce apoptosis and weakly activate the NF-kappaB transcription factor. |
TANK | TANK; TRAF-Interacting Protein; TRAF Family Member-Associated NF-Kappa-B Activator; TRAF2; I-TRAF; ITRAF | 10010 | Q92844 | Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2. |
TRADD | TRADD; TNFR1-Associated Death Domain Protein; TNFRSF1A-Associated Via Death Domain; TNFR1-Associated DEATH Domain Protein; Tumor Necrosis Factor Receptor-1-Associated Protein; Tumor Necrosis Factor Receptor Type 1-Associated DEATH Domain Protein; Tumor Ne | 8717 | Q15628 | The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B. |
TRAF1 | TRAF1; EBI6; Epstein-Barr Virus-Induced Protein 6; TNF Receptor-Associated Factor 1; MGC:10353; Epstein-Bar Virus-Induced Protein 6 | 7185 | Q13077 | The protein encoded by this gene is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from various receptors of the TNFR superfamily. This protein and TRAF2 form a heterodimeric complex, which is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein complex formed by this protein and TRAF2 also interacts with inhibitor-of-apoptosis proteins (IAPs), and thus mediates the anti-apoptotic signals from TNF receptors. The expression of this protein can be induced by Epstein-Barr virus (EBV). EBV infection membrane protein 1 (LMP1) is found to interact with this and other TRAF proteins; this interaction is thought to link LMP1-mediated B lymphocyte transformation to the signal transduction from TNFR family receptors. Three transcript variants encoding two different isoforms have been found for this gene. |
YWHAG | DEE56; EIEE56; PPP1R170; 14-3-3GAMMA | 7532 | P04637 | This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the rat ortholog. It is induced by growth factors in human vascular smooth muscle cells, and is also highly expressed in skeletal and heart muscles, suggesting an important role for this protein in muscle tissue. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. |
YWHAH | Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Eta; Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein, Eta Polypeptide; 14-3-3 Eta; YWHA1; 14-3-3 Protein Eta; Protein AS1 | 7533 | Q04917 | This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and bovine orthologs. This gene contains a 7 bp repeat sequence in its 5' UTR, and changes in the number of this repeat have been associated with early-onset schizophrenia and psychotic bipolar disorder. |
YWHAQ | 1C5; HS1; 14-3-3 | 10971 | P27348 | This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse and rat orthologs. This gene is upregulated in patients with amyotrophic lateral sclerosis. It contains in its 5' UTR a 6 bp tandem repeat sequence which is polymorphic, however, there is no correlation between the repeat number and the disease. |
YWHAZ | HEL4; YWHAD; KCIP-1; HEL-S-3; POPCHAS; HEL-S-93; 14-3-3-zeta | 7534 | P63104 | This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5' UTR but that encode the same protein have been identified for this gene. |
CAT | Product Name | Biomarker | Assay | Image |
ZG-0061J | Mouse Anti-CALD1 Recombinant Antibody (ZG-0061J) | CALD1 | IHC |
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ZG-0326J | Mouse Anti-FADD Recombinant Antibody (ZG-0326J) | FADD | WB |
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ZG-0327J | Mouse Anti-FADD Recombinant Antibody (ZG-0327J) | FADD | WB |
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ZG-0328J | Mouse Anti-FADD Recombinant Antibody (ZG-0328J) | FADD | WB |
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ZG-0144U | Mouse Anti-MFGE8 Recombinant Antibody (clone 2B2D10) | MFGE8 | IHC |
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ZG-0254U | Mouse Anti-YWHAZ Recombinant Antibody (clone 19G7E9) | YWHAZ | WB |
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VS3-FY181 | Recombinant Rabbit Anti-CALD1 Antibody (clone R05-3D2) | CALD1 | WB |
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VS3-FY182 | Recombinant Mouse Anti-CALD1 Antibody (clone 9B7-7G7-7A1) | CALD1 | IHC |
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VS3-FY532 | Recombinant Rabbit Anti-Fadd Antibody (clone R05-1K1) | Fadd | WB |
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VS3-FY533 | Recombinant Rabbit Anti-FADD Antibody (clone R02-1A6) | FADD | WB |
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VS3-FY1268 | Recombinant Rabbit Anti-RIPK1 Antibody (clone R07-8K8) | RIPK1 | WB |
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For research use only. Not intended for any clinical use.
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