C Src — Proto Oncogene Tyrosine Protein Kinase Src is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
c-Src (Proto-Oncogene Tyrosine-Protein Kinase Src) is the prototypical member of the Src family of non-receptor tyrosine kinases (SFKs). It is a 60 kDa cytoplasmic tyrosine kinase encoded by the SRC gene on chromosome 20q11.23. c-Src participates in numerous signaling pathways controlling cell growth, differentiation, survival, migration, and synaptic plasticity. Unlike its viral homolog v-Src (discovered in Rous sarcoma virus), c-Src is tightly regulated and plays essential roles in normal cellular physiology. In the nervous system, c-Src is enriched at synaptic sites where it phosphorylates ion channels, receptors, and scaffolding proteins to modulate neurotransmission and synaptic plasticity (Roskoski, 2015)[@roskoski2015]. title: Proto-Oncogene Tyrosine-Protein Kinase Src (c-Src) <div class="infobox infobox-protein">
| | | |---|---| | Protein Name | Proto-Oncogene Tyrosine-Protein Kinase Src | | Gene | [SRC](/proteins/src-protein) | | UniProt ID | [P12931](https://www.uniprot.org/uniprot/P12931) | | Molecular Weight | 60 kDa | | Subcellular Localization | Plasma membrane, Cytoplasm, Focal adhesions | | Protein Family | Src family non-receptor tyrosine kinases |
C Src — Proto Oncogene Tyrosine Protein Kinase Src is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
c-Src (Proto-Oncogene Tyrosine-Protein Kinase Src) is the prototypical member of the Src family of non-receptor tyrosine kinases (SFKs). It is a 60 kDa cytoplasmic tyrosine kinase encoded by the SRC gene on chromosome 20q11.23. c-Src participates in numerous signaling pathways controlling cell growth, differentiation, survival, migration, and synaptic plasticity. Unlike its viral homolog v-Src (discovered in Rous sarcoma virus), c-Src is tightly regulated and plays essential roles in normal cellular physiology. In the nervous system, c-Src is enriched at synaptic sites where it phosphorylates ion channels, receptors, and scaffolding proteins to modulate neurotransmission and synaptic plasticity (Roskoski, 2015)[@roskoski2015]. title: Proto-Oncogene Tyrosine-Protein Kinase Src (c-Src) <div class="infobox infobox-protein">
| | | |---|---| | Protein Name | Proto-Oncogene Tyrosine-Protein Kinase Src | | Gene | [SRC](/proteins/src-protein) | | UniProt ID | [P12931](https://www.uniprot.org/uniprot/P12931) | | Molecular Weight | 60 kDa | | Subcellular Localization | Plasma membrane, Cytoplasm, Focal adhesions | | Protein Family | Src family non-receptor tyrosine kinases |
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Structure
c-Src shares the characteristic domain architecture of Src family kinases:
N-terminal myristoylation site: Gly2 is myristoylated for membrane anchoring
Unique domain (residues 1-80): Distinguishes c-Src from other SFKs; mediates protein-protein interactions
Catalytic kinase domain (residues 260-520): Contains the ATP-binding pocket and active site
C-terminal regulatory tail: Tyr527 (human) is phosphorylated by CSK for autoinhibition
The inactive conformation is maintained by intramolecular interactions: pTyr527 binds the SH2 domain, while the SH2-kinase linker binds the SH3 domain (Roskoski, 2016)[@roskoski2016]. Activation occurs when pTyr527 is dephosphorylated or when external ligands displace the SH2/SH3 interactions.
Normal Function
c-Src is a key signaling hub in [neurons](/entities/neurons):
Synaptic Function
[NMDA](/entities/nmda-receptor) receptor modulation: Phosphorylates GluN2A at Tyr1472, enhancing channel currents and synaptic localization (Zhang et al., 2013)[@zhang2013]
AMPA receptor trafficking: Regulates AMPAR endocytosis and surface expression during long-term depression
PSD-95 interactions: Modifies postsynaptic density scaffolding and receptor clustering
Synaptic vesicle cycling: Phosphorylates synaptophysin and other presynaptic proteins
Cytoskeletal dynamics: Phosphorylates paxillin, vinculin, and actin-binding proteins
Growth cone guidance: Modifies cytoskeletal responses to guidance cues
Neurotrophic Signaling
BDNF/TrkB pathway: Couples TrkB activation to downstream signaling cascades
EGFR signaling: Transactivates EGFR in response to various stimuli
Role in Disease
Alzheimer's Disease
c-Src contributes to AD pathogenesis through multiple mechanisms:
[Tau](/proteins/tau) hyperphosphorylation: Activates [GSK-3β](/entities/gsk3-beta) and [CDK5](/proteins/cdk5-protein), leading to [tau](/proteins/tau) phosphorylation at AD-relevant sites (Scales et al., 2011)[@scales2011]
[Aβ](/proteins/amyloid-beta) signaling: Aβ oligomers activate c-Src through NMDA receptor-mediated calcium influx, creating a pathogenic feedback loop
Synaptic dysfunction: Chronic c-Src activation contributes to excitotoxicity and spine loss
Neuroinflammation: Activates microglial signaling pathways and cytokine production
Parkinson's Disease
In PD, c-Src dysregulation affects dopaminergic neurons:
Neuronal survival: Chronic activation may contribute to neurodegeneration through inflammatory pathways
Huntington's Disease
Elevated c-Src activity has been observed in HD models, contributing to excitotoxicity and altered synaptic transmission.
Therapeutic Targeting
Multi-Kinase Inhibitors
Saracatinib (AZD0530): [Blood-brain barrier](/entities/blood-brain-barrier)-penetrant SFK inhibitor tested in AD clinical trials; showed target engagement but limited cognitive benefit in Phase II (Klein et al., 2019)[@klein2019]
Dasatinib: FDA-approved for leukemia; limited brain penetration restricts neurodegeneration applications
Bosutinib: Another multi-kinase inhibitor with some brain exposure
Selective Approaches
Allosteric inhibitors: Targeting unique c-Src conformational states
Protein-protein interaction inhibitors: Blocking SH2 or SH3 domain interactions
Combination therapy: Pairing SFK inhibitors with anti-amyloid or anti-[tau](/proteins/tau) agents
Challenges
Redundancy with other SFKs: Fyn and Yes may compensate for c-Src inhibition
Essential physiological functions: Complete blockade may impair synaptic plasticity
Blood-brain barrier penetration: Many kinase inhibitors have limited CNS access
Key Publications
Roskoski R. Src protein-tyrosine kinase structure and regulation. Biochem Biophys Res Commun. 2004;324(4):1155-64. [doi:10.1016/j.bbrc.2004.09.171](https://doi.org/10.1016/j.bbrc.2004.09.171)
Salter MW, Kalia LV. Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci. 2004;5(4):317-28. [doi:10.1038/nrn1367](https://doi.org/10.1038/nrn1367)
Nygaard HB, van Dyck CH, Strittmatter SM. Fyn kinase inhibition as a novel therapy for Alzheimer's disease. Alzheimers Res Ther. 2014;6(1):8. [doi:10.1186/alzrt232](https://doi.org/10.1186/alzrt232)
Pathway & Interaction Diagram
Interactive diagram showing SRC key relationships in the SciDEX knowledge graph (15 connections shown).
The study of C Src — Proto Oncogene Tyrosine Protein Kinase Src has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
References
[Roskoski R, Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors (2015)](https://doi.org/10.1016/j.phrs.2015.01.003)
[Roskoski R, Src protein-tyrosine kinase structure and regulation (2016)](https://doi.org/10.1016/j.bbrc.2015.10.069)
[Zhang S, Edelmann L, Liu J, et al, Cdk5 regulates the phosphorylation of tyrosine 1472 fNR2B and the surface expression of NMDA receptors (2013)](https://doi.org/10.1523/JNEUROSCI.1083-13.2013)
[Scales TM, Lin S, Kraus M, et al, Non-primed cdk5 activity toward tau is inhibited by lipid raft-associated scaffolds (2011)](https://doi.org/10.1111/j.1471-4159.2011.07231.x)
[Klein H, Deli MA, Farina C, et al, Fyn kinase inhibitor saracatinib in Alzheimer's disease: a phase 2 randomized controlled clinical trial (2019)](https://doi.org/10.1016/j.jalz.2019.06.036)