Search results for F9

Showing 21 results out of 78

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Protein (5 results from a total of 57)

Identifier: R-HSA-159765
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: F9: P00740
Identifier: R-HSA-158225
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: F9: P00740
Identifier: R-HSA-9672455
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: P00740
Identifier: R-HSA-9671012
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: P00740
Identifier: R-HSA-9631373
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: P00740

Set (4 results from a total of 4)

Identifier: R-HSA-9673225
Species: Homo sapiens
Compartment: extracellular region
Identifier: R-HSA-9670852
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Identifier: R-HSA-9670837
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-9673245
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen

Reaction (5 results from a total of 10)

Identifier: R-HSA-9670888
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
In healthy individuals, the coagulation factor IX (FIX) is synthesized as a 461 amino acid precursor (primarily in the liver) and then secreted into plasma where it converts factor X to its active form. FIX zymogen undergoes extensive co- and post-translational modifications, including but not limited to glycosylation and γ-carboxylation. A deficiency or dysfunction of FIX caused by mutations in the F9 gene is associated with a blood clotting disorder hemophilia B (HB). The FIX protein level may be decreased in the circulation by F9 mutations affecting FIX protein synthesis, stability, or secretion. The carboxyl-terminal region of FIX contains several natural missense mutations such as Y450C, W453R and T458K, which impair secretion of FIX and result in mild to severe forms of HB (Kurachi S et al. 1997; Branchini A et al. 2013). In addition, exon 5 of the F9 gene contains dense splicing regulatory information that overlap with the amino acid code (Tajnik M et al. 2016). Under normal conditions exon 5 is correctly recognized by the spliceosome and mostly included in the final transcript. This leads to the production of a normal FIX protein that folds correctly in the endoplasmic reticulum (ER) and is efficiently secreted into the blood to activate coagulation. Several F9 mutations in exon 5 result in exon skipping (Tajnik M et al. 2016; Odaira K et al. 2019; Katneni UK et al. 2019). The exonic splicing mutations (ESM) can be divided into three major groups which define their molecular basis. In the first group, two synonymous variants, V153V and R162R, affect binding of splicing factors and induce severe exon skipping with the production of a non-functional mRNA (Tajnik M et al. 2016). The second type of ESM, such as A164V and Q167H, showed partial splicing defects producing low amounts of normally spliced transcript that, when translated, resulted in a defective FIX protein with a significantly reduced, but not completely abolished, secretion. However, the lower amounts of the secreted proteins maintained a normal specific coagulant activity. Lastly, mutation L163F (ESM group 3) showed a splicing defect but the resulting amino acid change severely affected FIX secretion (Tajnik M et al. 2016). Another HB-associated F9 variant caused abnormal mRNA splicing, r.83_88del, and produced the mutant FIX protein (p.C28_V30delinsF), which is an in-frame mutant at the signal peptide cleavage site (Odaira K et al. 2019). The FIX C28_V30delinsF variant was found to be retained in the ER without being secreted (Odaira K et al. 2019). Studies also showed defective secretion of HB-associated F9 nonsense mutations such as R294*, R298* and R384* (Branchini A et al. 2017; Pinotti M et al. 2012). The mechanism through which nonsense mutations impair gene expression and cause human genetic disease consists of premature translation termination, and the synthesis of truncated proteins with loss‐of‐function features (Mort M et al. 2008). These mutations can trigger nonsense‐mediated decay of mRNA, that degrades mRNA transcripts that harbor a premature translation-termination codon (PTC), thus reducing the synthesis of truncated proteins (Khajavi et al. 2006; Kurosaki T & Maquat LE 2016). However, the mechanism of ribosome readthrough, which consists of misrecognition of the premature stop codon by an aminoacyl‐tRNA instead of the termination factors can restore translation impaired by nonsense mutations (Rospert S et al. 2005). The occurrence of spontaneous ribosome readthrough over F9 R294* and F9 R298* nonsense mutations led to the synthesis of traces of full‐length FIX in HB patients (Pinotti M et al. 2012). A drug-induced ribosome readthrough targeting nonsense variants is considered as a potential treatment of inherited coagulation factor disorders (Branchini A et al. 2017; Ferrarese M et al. 2018; Balestra D & Branchini A 2019).

The Reactome event describes intracellular accumulation and/or decreased secretion of FIX due to different HB-related genetic alterations spread throughout the F9 gene. The F9 variants are described in relation to changes in the protein sequence. Defective splicing events induced by F9 mutations are not shown here.

Identifier: R-HSA-159803
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen, endoplasmic reticulum membrane
GGCX (gamma glutamyl carboxylase) in the endoplasmic reticulum gamma-carboxylates twelve glutamate residues on 3D-F9(29-461) (pro-factor IX). MK4 (vitamin K hydroquinone) is oxidized to MK4 epoxide in the process (Berkner 2000; Furie et al. 1999; Stenina et al. 2001; Morris et al. 1995; Ware et al. 1989).
Identifier: R-HSA-9673231
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen, endoplasmic reticulum membrane
Being a vitamin K‐dependent (VKD) glycoprotein, factor IX (FIX) is synthesized first as a precursor protein which then undergoes extensive posttranslational modification including γ-carboxylation. The precursor FIX protein has the following parts, starting with a signal peptide at the amino-terminal end, which directs the protein to the endoplasmic reticulum (ER), and continuing with the 18 residue length propeptide. The propeptide contains the γ‐carboxylase recognition site (γ‐CRS) in the N‐terminal part of the propeptide for connecting substrate to the gamma-glutamyl carboxylase (GGCX), and a peptidase recognition site in the C‐terminal for cleaving by PACE/furin (Higgins‐Gruber SL et al. 2010). GGCX in the ER γ-carboxylates twelve glutamate residues on F9(29-461) (pro-factor IX) converting the specific glutamic acids in the GLA domain to γ‐carboxyglutamic acid residues. MK4 (vitamin K hydroquinone) is oxidized to MK4 epoxide in the process (Berkner KL 2000; Furie B et al. 1999; Stenina O et al. 2001; Morris DP et al. 1995; Ware J et al. 1989). The signal peptide and the propeptide sequence of FIX are removed before the protein is secreted into the circulation,

Naturally occurring hemophilia B (HB)-associated point mutations in the FIX propeptide sequence such as F9 N43Q/L or F9 N46S reduce affinity to GGCX resulting in reduced γ-carboxylation and aberrant propeptide processing (Bentley AK et al. 1986; Rabiet MJ et al. 1987; Diuguid DL et al. 1986; Ware J et al. 1989; de la Salle C et al. 1993). FIX variants are secreted into the circulation with a mutant 18-amino acid propeptide still attached (Bentley AK et al. 1986; Galeffi P & Brownlee GG 1987). However, unprocessed FIX variants showed altered phospholipid binding properties and delayed activation by factor XIa (Liddell MB et al. 1989; Ware J et al. 1989; de la Salle C et al. 1993; Wojcik EG et al. 1997; Bristol JA et al. 1993, 1994). In addition, beta-hydroxylation of aspartic acid 110 (D110) is an independent process which does not require vitamin K and is mediated through a hydroxylation recognition site in the mature Factor IX, not in the propeptide (Rabiet MJ et al. 1987).

The Reactome event describes defective γ-carboxylation of FIX variants due to HB-associated genetic defects in the propeptide sequence of the F9 gene.

Identifier: R-HSA-4086393
Species: Homo sapiens
Compartment: plasma membrane
Signaling by WNT5A and FZD2 activates PDE6 through G protein alpha subunit t2 (Liu et al, 1999; Ahumada et al, 2002). The discovery that G alpha t2 is involved in WNT:Ca2+ signaling was surprising, as this G protein subunit is best characterized for its role in visual transduction and its expression in vertebrates is almost exclusively restricted to the visual pathway (reviewed in Wang et al, 2004). Recent work in the WNT field has shown that a pathway similar to the visual transduction cascade exists in the mouse F9 teratocarcinoma cell line, CHO cells, zebrafish embryos as well as in a number of human cancer cell lines (Liu et al, 1999; Ahumada et al, 2002; Bazhin et al, 2010). PDE6 is a tetramer of two catalytic subunits, alpha and beta, held in an inactive conformation by two regulatory gamma subunits. Recruitment and binding with G alpha t2 relaxes the inhibitory effect of PDE6gamma and allows activation of the catalytic subunits (reviewed in Wensel, 2008). Activation of PDE6 in the WNT pathway may also depend on p38 MAPK (Ma and Wang, 2007).
Identifier: R-HSA-3965441
Species: Homo sapiens
Compartment: plasma membrane, extracellular region
Studies with FZD receptors in zebrafish, Xenopus and mouse teratocarcinoma cells suggest that G-proteins are involved in signal transduction downstream of WNT5A/WNT11 signaling. Disrupting the function of G-protein alpha 0 and t2 subunits abrogates FZD-dependent calcium release and activation of potential downstream targets such as PKC, CaMK2 and calcineurin (Slusarski et al, 1997; Liu et al, 1999; Penzo-Mendez et al 2002; reviewed in Malbon et al, 2001; Angers and Moon, 2009)

Pathway (5 results from a total of 5)

Identifier: R-HSA-9673218
Species: Homo sapiens
A deficiency or dysfunction of factor IX (FIX) caused by mutations in the F9 gene is associated with a blood clotting disorder hemophilia B (HB). The FIX protein level may be decreased in the circulation by F9 mutations affecting FIX protein synthesis, stability, or secretion (Kurachi S et al. 1997; Enjolras N et al. 2004; Branchini A et al. 2013, 2017; Tajnik M et al. 2016; Odaira K et al. 2019).

The Reactome event describes intracellular accumulation and/or decreased secretion of FIX due to different HB-related genetic alterations spread throughout the F9 gene.

Identifier: R-HSA-9673240
Species: Homo sapiens
Naturally occurring hemophilia B (HB)-associated point mutations in the FIX propeptide sequence reduce affinity to gamma-glutamyl carboxylase (GGCX) resulting in reduced γ-carboxylation and aberrant propeptide processing (Bentley AK et al. 1986; Rabiet MJ et al. 1987; Diuguid DL et al. 1986; Ware J et al. 1989; de la Salle C et al. 1993). Unprocessed FIX variants such as F9 N43Q/L or F9 N46S, circulate with the attached propeptide and show delayed FIX activation (Bentley AK et al. 1986; Diuguid DL et al. 1986; Ware J et al. 1989; de la Salle C et al. 1993).
Identifier: R-HSA-9673221
Species: Homo sapiens
Deficiency or dysfunction of FIX leads to hemophilia B (HB), an X-linked, recessive, bleeding disorder. On a molecular basis, HB is due to a heterogeneous spectrum of mutations spread throughout the F9 gene (Rallapalli PM et al. 2013).

The Reactome event describes the defective proteolytic activation of FIX by factor XIa due to the presence of HB-associated point mutations R191C, R191H, R226Q and R226W in the cleavage sites of FIX (Liddell MB et al. 1989; Monroe DM et al. 1989; Suehiro K et al. 1989; Diuguid DL et al. 1989; Bertina RM et al.1990). In addition, naturally occurring point mutations in the FIX propeptide sequence such as N43Q, N43L or N46S are also annotated here. These FIX variants are secreted into the circulation with a mutant 18-amino acid propeptide still attached (Bentley AK et al. 1986; Galeffi P & Brownlee GG 1987). The unprocessed FIX variants were found to affect the function of the protein by destabilizing the calcium-induced conformation of FIX (Wojcik EG et al. 1997) and showed delayed activation by FXIa (Liddell MB et al. 1989; Ware J et al. 1989; de la Salle C et al. 1993; Wojcik EG et al. 1997; Bristol JA et al. 1993).


Identifier: R-HSA-9673202
Species: Homo sapiens
Factor IX (FIX) deficiency is associated with mild to severe bleeding in hemophilia B (HB) patients (Rallapalli PM et al. 2013). HB is caused by a wide range of mutations that can include point mutations (nonsense and missense), insertions, deletions and other complex rearrangements of the F9 gene (Rallapalli PM et al. 2013). The Reactome event describes failed generation of FXa as the functional consequence of the defective serine protease activity of hemophilia B (HB)-associated FIX variants such as G363R & G363E (Lu Q et al. 2015), G357E (Miyata T et al. 1991), A436V (Usharani P et al. 1985), I443T (Hamaguchi N et al. 1991), G409V (Bajaj SP et al. 1990), D410H and S411G (Ludwig M et al. 1992).
Identifier: R-HSA-9668250
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
The F9 gene encodes coagulation factor IX (FIX), a vitamin K-dependent plasma protease that participates in the intrinsic blood coagulation pathway. FIX circulates as a zymogen, and is proteolytically activated to FIXa by activated FXIa or tissue factor-bound FVIIa. After being activated, FIXa forms a complex with Ca2+ ions, membrane phospholipids and coagulation factor VIIIa to activate coagulation factor X. Mutations within F9 gene that lead to quantitative and/or qualitative deficiencies in the circulating FIX protein are associated with hemophilia B (HB), a rare X-linked, recessively transmitted bleeding disorder (White GC et al. 2001; Rallapalli PM et al. 2013; Goodeve AC 2015). The disease severity in hemophilia is classified according to the plasma procoagulant levels of FIX activity. The severe form is defined as a factor level <1% of normal, the moderate form as a factor level of 1-5%, and the mild form with a factor level >5 and <40%. Patients with severe hemophilia frequently develop hemorrhages into joints, muscles or soft tissues without any apparent cause. They can also suffer from life-threatening bleeding episodes such as intracranial hemorrhages. Persons with mild and moderate factor deficiency rarely experience spontaneous hemorrhages, and excessive bleeding mostly occurs only following trauma or in association with invasive procedures.

A wide range of different genetic alterations are spread throughout the F9 gene, including single nucleotide substitutions, small and large deletions (Rallapalli PM et al. 2013). However functional consequences of most F9 mutations are poorly studied. The Reactome event describes altered functions of HB-associated FIX variants such as reduced FIX protein secretion due to defective expression and/or processing, failed proteolysis of factor X to Xa by defective FIX and failed formation of a membrane complex in the presence of Ca2+ ions, phospholipid, and cofactor VIIIa. The annotated HB-associated FIX variants are supported with data from functional studies (Usharani P et al. 1985; Spitzer SG et al. 1990; Ludwig M et a. 1992; Kurachi S et al. 1997; Branchini A et al. 2013).

Complex (1 results from a total of 1)

Identifier: R-HSA-9670846
Species: Homo sapiens
Compartment: plasma membrane

Icon (1 results from a total of 1)

F9

Species: Homo sapiens
Curator: Bruce May
Designer: Cristoffer Sevilla
F9 icon
Coagulation factor IX
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