FYN

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Protein-coding gene in humans

title: "FYN" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["tyrosine-kinases"] description: "Protein-coding gene in humans" topic_path: "general/tyrosine-kinases" source: "https://en.wikipedia.org/wiki/FYN" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in humans ::

Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the FYN gene.

Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neuronal signaling in development and normal cell physiology. Disruptions in these signaling pathways often have implications in the formation of a variety of cancers. By definition as a proto-oncogene, Fyn codes for proteins that help regulate cell growth. Changes in its DNA sequence transform it into an oncogene that leads to the formation of a different protein with implications for normal cell regulation.

Fyn is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist.

History

Fyn is a member of the Src-family of kinases (SFK), the first proto-oncogene to be identified. The discovery of the Src-family in 1976 led to the Nobel prize for medicine in 1989 for J.M Bishop and E.M. Varmus. Fyn was first identified in 1986 as Syn or Slk through probes derived from v-yes and v-fgr. A common feature of SFKs is that they are commonly upregulated in cancers. Fyn is functionally distinct from its family members in that it interacts with FAK and paxillin (PXN) in the regulation of cell morphology and motility.

Function

Fyn is a protein, present in the signaling pathway of integrins, which activates ras. Fyn is a tyrosine-specific phospho-transferase that is a member of the Src family of non-receptor tyrosine protein kinases. (This family also includes Abl, Src, focal adhesion kinase and Janus kinase.) Fyn is located downstream of several cell surface receptors, commonly associated with neuronal development and T-cell signaling. When fyn is activated it causes downstream activation of molecular signals that drive processes crucial to growth and motility of cells. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane, where it phosphorylates tyrosine residues on key targets involved in a variety of different signaling pathways. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. Fyn also is a tumor suppressor. When this normal biology is compromised, the altered Fyn becomes involved in the neoplastic transformation of normal cells to cancerous ones following the pathway from pre-invasive, to invasive, and ultimately metastasis.

Fyn also appears to play an important role in fertilization including in the rapid Inositol trisphosphate-mediated calcium signaling which occurs when oocyte and sperm interact. Fyn expression levels are much higher in oocytes than even neurons and T-cells and it has been suggested to be an 'oocyte-specific kinase'. Several studies point to Fyn as being responsible for dramatic biochemical changes in the oocyte cortex during oocyte maturation. Fyn may also play an important role in proper shaping of sperm head and acrosome within the testis and possibly has an additional role in the sperm acrosome reaction.

Role in signaling pathways

An understanding of the role of fyn in normal biology is crucial to the understanding of its role in cancer, as cancer is the dysregulation of these normal pathways. Knowing which pathways involve Fyn will provide key insight for the development of potential pharmacologic agents to attenuate this uncontrolled signaling.

At least three tools have been useful in discerning a requirement for Fyn function in a particular signaling system:

cells derived from Fyn-/- mice (as well as cells derived from Fyn, Src, Yes, Fyn triple knockout mice (SYF));
a kinase-inactive, dominant negative mutant form of Fyn (K299M);
pharmacologic inhibitors of Src family kinases, such as PP2; note that PP2 also inhibits other tyrosine protein kinases such as Abl, PDGFR and c-Kit.

Using these tools, a requirement for Fyn has been shown for the following signaling pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. Fyn also has an important role to play in TLR-mediated immune responses from T cells.

Interactions

FYN has been shown to interact with:

Role in cancer biology

The Src family of kinases is commonly associated with its role in "invasion and tumor progression, epithelial-to-mesenchymal transition, angiogenesis, and development of metastasis," all hallmarks of cancer progression. Fyn's normal function in cellular growth and proliferation has the potential to be exploited in the progression and metastasis of cancer cells. Overexpression of Fyn has been found to drive morphologic transformation in normal cells and increase "anchorage-independent growth and prominent morphologic changes."

Fyn overexpression has been studied in relation to the following cancers: prostate cancer, glioblastoma multiform, squamous cell carcinoma of the head and neck, pancreatic cancer, chronic melogenic leukemia, and melanoma. This overexpression triggers a promotion of "anti-apoptotic activity of Akt" in prostate cancer, meaning that these cells have gained the ability to avoid the normal cell death pathways (a common hallmark of cancer). Additionally, in glioblastoma multiform, Src and Fyn have been found to be "effectors of oncogenic EGFR signaling" which has led to tumor invasion and cancer cell survival.

Fyn's normal role in cell migration and adhesion enables it to utilize the normal cell biology of integrin and FAK for cancer growth. Normal integrin is a cell surface receptor that interacts with the extracellular matrix to send signals influencing cell shape and motility. Normal FAK is a tyrosine kinase that gets recruited to focal adhesion sites and plays a key role in directed cell movement. These normal pathways plan a key role in "mediation of Fyn transmitted cellular events impacting shape and motility." A compromised version of this pathway would enable cancer cells to change shape and motility, increasing the possibility for advanced invasion and metastasis. Additional pathways under investigation regarding Fyn's role in cancer progression include: the Rac and Rho family of GTPases, Ras, Erk, and MAPK.

Because of this, Fyn has been a common target for anti-cancer therapeutic research. The inhibition of Fyn (like other SFKs) results in decreased cell growth. Furthermore, "expression of kinase-dead-Fyn (KD-Fyn), a specific competitor of endogenous Fyn," was found to reduce the size of primary tumors in mice. Specifically targeting the unique identifying properties of Fyn as well as inhibiting FAK and PXN has the potential to create a very effective molecularly targeted combination cancer therapy. Fyn inhibitors are also being explored as potential therapies for Alzheimer's Disease.

References

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(September 2003). "Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia". Neuroscience Letters.
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(November 1999). "A catalytically active Jak2 is required for the angiotensin II-dependent activation of Fyn". Journal of Biological Chemistry.
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(March 1997). "Interaction between Sam68 and Src family tyrosine kinases, Fyn and Lck, in T cell receptor signaling". Journal of Biological Chemistry.
(Sep 2008). "Lck-dependent Fyn activation requires C terminus-dependent targeting of kinase-active Lck to lipid rafts". The Journal of Biological Chemistry.
(2014). "Disruption of Fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase". PLOS ONE.
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(June 2003). "Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin". Journal of Biological Chemistry.
(May 2000). "Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation". The Journal of Experimental Medicine.
(December 1992). "Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system". The Biochemical Journal.
(July 1999). "Direct interaction in T-cells between thetaPKC and the tyrosine kinase p59fyn". Journal of Biological Chemistry.
(March 1997). "RAFTK, a novel member of the focal adhesion kinase family, is phosphorylated and associates with signaling molecules upon activation of mature T lymphocytes". The Journal of Experimental Medicine.
(June 2000). "Protein-tyrosine kinase Pyk2 is involved in interleukin-2 production by Jurkat T cells via its tyrosine 402". Journal of Biological Chemistry.
(April 1997). "Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling". The Journal of Experimental Medicine.
(January 2003). "Specific interactions of neuronal focal adhesion kinase isoforms with Src kinases and amphiphysin". Journal of Neurochemistry.
(May 2001). "The role of the Src homology 3-Src homology 2 interface in the regulation of Src kinases". Journal of Biological Chemistry.
(Nov 2009). "Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn". The EMBO Journal.
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(June 2003). "p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn". Biochemical and Biophysical Research Communications.
(February 2003). "Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors". Journal of Biological Chemistry.
(February 2003). "SAP couples Fyn to SLAM immune receptors". Nature Cell Biology.
(October 1998). "Molecular interaction between the Fyn-associated protein SKAP55 and the SLP-76-associated phosphoprotein SLAP-130". Journal of Biological Chemistry.
(June 1997). "Molecular cloning of SKAP55, a novel protein that associates with the protein tyrosine kinase p59fyn in human T-lymphocytes". Journal of Biological Chemistry.
(October 2002). "SKAP55 recruits to lipid rafts and positively mediates the MAPK pathway upon T cell receptor activation". Journal of Biological Chemistry.
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(February 2001). "Stimulation of M3 muscarinic receptors induces phosphorylation of the Cdc42 effector activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway". Journal of Biological Chemistry.
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(June 1997). "Interaction of p59fyn with interferon-activated Jak kinases". Biochemical and Biophysical Research Communications.
(February 2002). "Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau". The Journal of Neuroscience.
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(October 1995). "Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains". Molecular and Cellular Biology.
(June 1995). "Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins". Molecular and Cellular Biology.
(2011-05-01). "Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration". Molecular Carcinogenesis.
(2015). "A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease". Alzheimer's Research & Therapy.

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