Persius/hicric huggingface dataset:
ErbB

# Overview
The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease.
In mice loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors.

# Family members
The ErbB protein family consists of 4 members
- ErbB-1, also named epidermal growth factor receptor (EGFR)
- ErbB-2, also named HER2 in humans and neu in rodents
- ErbB-3, also named HER3 and
- ErbB-4, also named HER4

# Structure
ErbB receptors are made up of an extracellular region which contains approximately 620 amino acids, a single transmembrane spanning region and a cytoplasmic tyrosine kinase domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2 and CR2, were "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2) and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV respectively.
The figure below was created using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4).

# Kinase activation
The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher order oligomers upon activation by a subset of potential growth factor ligands. 
There are 11 growth factors that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively.

# Role in cancer
ErbB-1 is overexpressed in many cancers. Drugs such as cetuximab, gefitinib, erlotinib are used to inhibit it. It has recently been shown that acquired resistance to the two first can be linked to hyperactivity of ErbB-3. 
This is linked to an acquired overexpression of c-MET which phosphorylates ErbB-3, which in turn activates the Akt pathway.
F13B
Coagulation factor XIII B chain is a protein that in humans is encoded by the F13B gene.
This gene encodes coagulation factor XIII B subunit. Coagulation factor XIII is the last zymogen to become activated in the blood coagulation cascade. Plasma factor XIII is a heterotetramer composed of 2 A subunits and 2 B subunits. The A subunits have catalytic function, and the B subunits do not have enzymatic activity and may serve as a plasma carrier molecules. Platelet factor XIII is composed of just 2 A subunits, which are identical to those of plasma origin. Upon activation by the cleavage of the activation peptide by thrombin and in the presence of calcium ion, the plasma factor XIII dissociates its B subunits and yields the same active enzyme, factor XIIIa, as platelet factor XIII. This enzyme acts as a transglutaminase to catalyze the formation of gamma-glutamyl-epsilon-lysine crosslinking between fibrin molecules, thus stabilizing the fibrin clot. Factor XIII deficiency is classified into two categories: type I deficiency, characterized by the lack of both the A and B subunits; and type II deficiency, characterized by the lack of the A subunit alone.  These defects can result in a lifelong bleeding tendency, defective wound healing, and habitual abortion.

# Interactions
F13B has been shown to interact with Coagulation factor XIII, A1 polypeptide.
FA2H
Fatty acid 2-hydroxylase is a protein that in humans is encoded by the FA2H gene.

# Function
This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups.

# Clinical significance
Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia as well as fatty acid hydroxylase-associated neurodegeneration.
FA2H has been shown to modulate cell differentiation in vitro. FA2H is may be a 9-THC-regulated gene, as 9-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.
FEZ1
Fasciculation and elongation protein zeta-1 is a protein that in humans is encoded by the FEZ1 gene.
This gene is an ortholog of the C. elegans unc-76 gene, which is necessary for normal axonal bundling and elongation within axon bundles. Expression of this gene in C. elegans unc-76 mutants can restore to the mutants partial locomotion and axonal fasciculation, suggesting that it also functions in axonal outgrowth. The N-terminal half of the gene product is highly acidic. Alternatively spliced transcript variants encoding different isoforms of this protein have been described.
This protein is present in neurons, and it is believed to block the process of infection of these cells by HIV.

# Interactions
FEZ1 has been shown to interact with Protein kinase M, NBR1 and DISC1.
FGF1
FGF1, also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene.  It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein.  Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using  different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1.  Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.
FGF-1 has no definitive signal sequence and thus is not secreted through classical pathways, but it does appear to form a disulfide linked dimer inside cells that associate with a complex of proteins at the cell membrane (including S100A13 and Syt1) which then help flip it through the membrane to the exterior of the cell.  Once in the reducing conditions of the surrounding tissue, the dimer dissociates into monomeric FGF1 that can enter systemic circulation or be sequestered in tissues binding to heparan sulfate proteoglycans of the extracellular matrix. FGF1 can then bind to and exert its effects via specific fibroblast growth factor receptor (FGFR) proteins which themselves constitute a family of closely related molecules.
In addition to its extracellular activity, FGF1 can also function intracellularly. The protein has a nuclear localization sequence (NLS) but the route that FGF1 takes to get to the nucleus is unclear and it appears that some sort of cell surface receptor binding is necessary, followed by its internalization and translocation to the nucleus whereupon it can interact with nuclear isoforms of FGFRs.  This is different from FGF2 which also can activate nuclear FGFRs but has splicing variants of the protein that never leave the cell and go directly to the nucleus.

# Function
FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein functions as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor. It acts as a mitogen for a variety of mesoderm- and neuroectoderm-derived cells in vitro, thus is thought to be involved in organogenesis. Three alternatively spliced variants encoding different isoforms have been described.
FGF1 is multifunctional with many reported effects.  For one example, in mice with diet-induced diabetes that is an experimental equivalent of type 2 diabetes in humans, a single injection of the FGF1 protein is enough to restore blood sugar levels to a healthy range for > 2 days.

# Interactions
FGF1 has been shown to interact with:
- CSNK2A2
- CSNK2B
- CSNK2A1
- FIBP
- FGFR1
- FGFR2
- FGFR3
- FGFR4
- HSPA9  and
- S100A13
- Synaptotagmin 1 (SYT1)
FGF3
INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the FGF3 gene.

# Function
FGF-3 is a member of the fibroblast growth factor family. FGF3 binds to Fibroblast Growth Factor Receptor 3 (FGFR3) to serve as a negative regulator of bone growth during ossification. Effectively, FGF-3 inhibits proliferation of chondrocytes within growth plate.
FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.

# Clinical significance
The FGF3 gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. Also, haploinsufficiency in the FGF3 gene is thought to cause otodental syndrome.

# Interactions
FGF3 (gene) has been shown to interact with EBNA1BP2.
FGF4
Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.

# Function
During embryonic development, the 21-kD protein FGF4 functions as a signaling molecule that is involved in many important processes. Studies using Fgf4 gene knockout mice showed developmental defects in embryos both in vivo and in vitro, revealing that FGF4 facilitates the survival and growth of the inner cell mass during the postimplantation phase of development by acting as an autocrine or paracrine ligand. FGFs produced in the apical ectodermal ridge (AER) are critical for the proper forelimb and hindlimb outgrowth. FGF signaling in the AER is involved in regulating limb digit number and cell death in the interdigital mesenchyme. When FGF signaling dynamics and regulatory processes are altered, postaxial polydactyly and cutaneous syndactyly, two phenotypic abnormalities collectively known as polysyndactyly, can occur in the limbs. Polysyndactyly is observed when an excess of Fgf4 is expressed in limb buds of wild-type mice. In mutant limb buds that do not express Fgf8, the expression of Fgf4 still results in polysyndactyly, but Fgf4 is also able to rescue all skeletal defects that arise from the lack of Fgf8. Therefore, the Fgf4 gene compensates for the loss of the Fgf8 gene, revealing that FGF4 and FGF8 perform similar functions in limb skeleton patterning and limb development. Studies of zebrafish Fgf4 knockdown embryos demonstrated that when Fgf4 signaling is inhibited, randomized left-right patterning of the liver, pancreas, and heart takes place, showing that Fgf4 is a crucial gene involved in developing left-right patterning of visceral organs. Furthermore, unlike the role of FGF4 in limb development, FGF4 and FGF8 have distinct roles and function independently in the process of visceral organ left-right patterning.
Fgf signaling pathway has also been demonstrated to drive hindgut identity during gastrointestinal development, and the up regulation of the Fgf4 in pluripotent stem cell has been used to direct their differentiation for the generation of intestinal Organoids and tissues in vitro.
FGF8
Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 gene.

# Function
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion.
Fgf8 is important and necessary for setting up and maintaining the midbrain/hindbrain border (or mesencephalon/met-encephalon border) which plays the vital role of organizer in development, like the Spemann organizer of the gastrulating embryo. Fgf8 is expressed in the region where Otx2 and Gbx2 cross inhibit each other and is maintained expression by this interaction. Once expressed, the Fgf8 induces other transcription factors to form cross-regulatory loops between cells, thus the border is established. Through development, the Fgf8 goes to regulate the growth and differentiation of progenitor cells in this region to produce ultimate structure of midbrain and hindbrain. Crosselys experiment proves that the Fgf8 is sufficient to induce the repatterning of midbrain and hindbrain structure.
In the development of forebrain, cortical patterning centers are the boundaries or poles of cortical primordium, where multiple BMP and WNT genes are expressed. Besides, at the anterior pole several FGF family including Fgf3, 8,17 and 18 overlap in expression. The similarity in cortical gene expression in Emx2 mutants and mice in which the anterior FGF8 source is augmented suggests that FGF8 controls the graded expression(low anterior, high posterior) of Emx2 in the cortical primordium. Emx2 is one of the protomap molecular determinants that prove to be closely interacted with Pax6. Emx2 and Pax6 are expressed in opposing gradients along the A/P axis of the cortical primordium and cooperate to set up area pattern. Fgf8 and Emx2 antagonize each other to create the development map. Fgf8 promotes the development of anterior part and suppresses posterior fate, while the Emx2 does the reverse. What's more, FGF8 manipulations suggest FGF8 controls the cortical graded expression of COUP-TF1. Moreover, the sharpness of both COUPTF1 and COUP-TF2 expression borders would be expected of genes involved in boundary specification.Thus, the interaction between them regulates the A/P axis of cortical primordium and directs the development map of cortical area.

# Clinical significance
This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogenesis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs reveal roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants.
FGF9
Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.

# Function
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis. This gene is involved in the patterning of sex determination, lung development, and skeletal development.

## Sex determination
FGF9 has also been shown to play a vital role in male sex development. FGF9s role in sex determination begins with its expression in the bi-potent gonads for both females and males. Once activated by SOX9, it is responsible for forming a feedforward loop with Sox9, increasing the levels of both genes. It forms a positive feedback loop upregulating SOX9, while simultaneously inactivating the female Wnt4 signaling pathway. The absence of Fgf9 causes an individual, even an individual with X and Y chromosomes, to develop into a female, as it is needed to carry out important masculinizing developmental functions such as the multiplication of Sertoli cells and creation of the testis cords.

## Lung development
In lung development, FGF9 is expressed in the mesothelium and pulmonary epithelium, where its purpose is to retain lung mesenchymal proliferation. Inactivation of FGF9 results in diminished epithelial branching. By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.

## Skeletal development
Another biological role presented by this gene is its involvement in skeletal development and repair. FGF9 and FGF18 both stimulate chondrocyte proliferation. FGF9 heterozygous mutant mice had a compromised bone repair after an injury with less expression of VEGF and VEGFR2 and lower osteoclast recruitment.  One disease associated with this gene is multiple synostoses syndrome (SYNS), a rare bone disease that has to do with the fusion of the fingers and toes. A missense mutation in the second exon of the FGF9 gene, the S99N mutation, seems to be the third cause of SYNS. A mutation in Noggin (NOG) and the Growth Differentiation Factor 5 (GDF5) are the other two causes of SYNS. The S99N mutation results in cell signaling irregularities that interfere with chondrogenesis and osteogenesis causing the fusion of the joints during development.

# Interactions
FGF9 has been shown to interact with Fibroblast growth factor receptor 3.
FGL1
Fibrinogen-like protein 1 (FGL-1) is a protein that is structurally related to fibrinogen. In humans, FLG-1 is encoded by the FGL1 gene. Four splice variants exist for this gene.

# Function
Fibrinogen-like protein 1 is a member of the fibrinogen family of proteins, which also includes fibrinogen, fibrinogen-like protein 2, and clotting factors V, VIII, and XIII. FGL-1 is homologous to the carboxy terminus of the fibrinogen beta- and gamma- subunits which contains the four conserved cysteines of that are common to all members of the fibrinogen family. However, FGL-1 lacks the platelet-binding site, cross-linking region, and thrombin-sensitive site which allow the other members of the fibrinogen family to aid in fibrin clot formation.

# Clinical significance
FGL-1 may play a role in the development of hepatocellular carcinomas.
FHIT
Bis(5'-adenosyl)-triphosphatase also known as fragile histidine triad protein (FHIT) is an enzyme that in humans is encoded by the FHIT gene.

# Function
FHIT is also known as human accelerated region 10.  It may, therefore, have played a key role in differentiating humans from apes.
This gene, a member of the histidine triad gene family, encodes a diadenosine  	
P1,P3-bis(5'-adenosyl)-triphosphate adenylohydrolase involved in purine metabolism. The gene encompasses the common fragile site FRA3B on chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts of this gene. In fact, aberrant transcripts from this gene have been found in about half of all esophageal, stomach, and colon carcinomas.
Though the exact molecular function of FHIT is still partially unclear, the gene works as a tumor suppressor as it has been demonstrated in animal studies. Furthermore FHIT has been shown to synergize with VHL, another tumor suppressor, in protecting against chemically - induced lung cancer.
FHIT also acts as a tumor suppressor of HER2/neu driven breast cancer.

# Interactions
FHIT has been shown to interact with UBE2I.
FHL1
Four and a half LIM domains protein 1 is a protein that in humans is encoded by the FHL1 gene.

# Structure
LIM proteins, named for 'LIN11, ISL1, and MEC3,' are defined by the possession of a highly conserved double zinc finger motif called the LIM domain.

# Role in muscle disorders
FHL1 has been shown to be heavily expressed in skeletal and cardiac muscles. In 2008 this was borne out by the discovery that defects in the FHL1 gene are responsible for a number of Muscular dystrophy-like muscle disorders, ranging from severe, childhood onset diseases through to adult-onset disorders similar to Limb girdle muscular dystrophy. At present different research groups are using different terminology for these disorders, which include:
FHL5
Four and a half LIM domains protein 5 is a protein that in humans is encoded by the FHL5 gene.

# Function
The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene.

# Interactions
FHL5 has been shown to interact with CREB1 and CAMP responsive element modulator.
FLI1
Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.

# Function
Fli-1 is a member of the ETS transcription factor family that was first identified in erythroleukemias induced by Friend Murine Leukemia Virus (F-MuLV). Fli-1 is activated through retroviral insertional mutagenesis in 90% of F-MuLV-induced erythroleukemias. The constitutive activation of fli-1 in erythroblasts leads to a dramatic shift in the Epo/Epo-R signal transduction pathway, blocking erythroid differentiation, activating the Ras pathway, and resulting in massive Epo-independent proliferation of erythroblasts. These results suggest that Fli-1 overexpression in erythroblasts alters their responsiveness to Epo and triggers abnormal proliferation by switching the signaling event(s) associated with terminal differentiation to proliferation.

# Clinical significance
In addition to Friend erythroleukemia, proviral integration at the fli-1 locus also occurs in leukemias induced by the 10A1, Graffi, and Cas-Br-E viruses. Fli-1 aberrant expression is also associated with chromosomal abnormalities in humans. In pediatric Ewings sarcoma a chromosomal translocation generates a fusion of the 5 transactivation domain of EWSR1 (also known as EWS) with the 3 Ets domain of Fli-1. The resulting fusion oncoprotein, EWS/Fli-1, acts as an aberrant transcriptional activator. with strong transforming capabilities. EWS/Fli-1 may steer clinically important genes via interaction with enhnacer-like GGAA-microsatellites. The importance of Fli-1 in the development of human leukemia, such as acute myelogenous leukemia (AML), has been demonstrated in studies of translocation involving the Tel transcription factor, which interacts with Fli-1 through protein-protein interactions. A recent study has demonstrated high levels of Fli-1 expression in several benign and malignant neoplasms using immunohistochemistry.
A possible association with Paris-Trousseau syndrome has been suggested.