LYN curation notes

Gene: LYN (HGNC), UniProt P07948, human. Src-family non-receptor protein
tyrosine kinase (p56Lyn/LynA and p53Lyn/LynB isoforms). EC 2.7.10.2.

Core identity and molecular function

LYN is a Src-family kinase (SFK) with the canonical SH4–unique–SH3–SH2–kinase(SH1)–
C-terminal-tail architecture. Its molecular function is ATP-dependent phosphorylation
of tyrosine residues in protein substrates (non-membrane-spanning protein tyrosine
kinase activity, GO:0004715).

• UniProt P07948 CATALYTIC ACTIVITY: "L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) ... EC=2.7.10.2".
• Domains (UniProt FT): SH3 63–123, SH2 129–226, protein kinase 247–501; ATP binding 253–261 and K275; active site D367.
• Regulation: autophosphorylation of activation-loop Tyr397 (required for optimal activity); CSK/MATK phosphorylation of C-terminal Tyr508 is inhibitory (SH2 clamp / closed conformation); dephosphorylation by CD45/PTPRC activates. [UniProt ACTIVITY REGULATION]
• Membrane targeting: Gly2 N-myristoylation + Cys3 S-palmitoylation → plasma membrane cytoplasmic face and lipid rafts. Traffics via Golgi. [15173188, 20605918, 18817770; UniProt LIPID features]

Substrate recognition and dual signaling role

LYN is a receptor-proximal signaling switch that phosphorylates BOTH activating ITAMs
and inhibitory ITIMs (dualistic role). [deep-research falcon; L'Estrange-Stranieri 2024 Front Immunol]

• ITAM/activating: "An initial signaling event following activation of the B cell antigen receptor is phosphorylation of the CD79a (Ig-alpha) ITAM by Lyn, a Src family protein-tyrosine kinase." PMID:10748115
• HS1/HCLS1 substrate: "p75HS1 showed rapid tyrosine phosphorylation and association with a Src-like kinase, Lyn, after crosslinking of membrane-bound IgM." PMID:7682714
• ITIM/inhibitory: phosphorylates CD22, FcγRIIB, PIR-B, SIRPα ITIMs → recruits SHP-1/SHP-2 and SHIP-1 phosphatases, restraining BCR/FcR signaling. UniProt: "Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM)". [UniProt FUNCTION]
• Dual: "Lyn appears to play a critical role in B cell receptor signaling due to its dual modulating capacity via activating or inhibiting downstream pathways" PMID:35941532

Substrates named in UniProt include BTK, CBL, CD5, CD19, CD22, CD72, CD79A, CD79B,
CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK, TEC, SIRPA, PTPN6, INPP5D, LPXN, SCIMP.

Localization

• Plasma membrane (cytoplasmic face) / lipid rafts — principal functional location. [IBA is_active_in; 12670955; 11313396]
• Golgi apparatus and perinuclear region — biosynthetic trafficking. "Lyn ... is biosynthetically transported to the plasma membrane via the Golgi pool of caveolin along the secretory pathway." PMID:15173188; "After synthesis in the cytoplasm, Lyn accumulates on the Golgi and is subsequently transported to the plasma membrane." PMID:20605918
• Nucleus — DNA-damage/kinase-inhibited pool. "Lyn was definitely detected in purified nuclei by immunofluorescence and immunoblotting analyses." PMID:18817770; "The cellular response to DNA damage includes activation of the nuclear Lyn protein tyrosine kinase." PMID:10891478
• Cytosol — many Reactome TAS rows record reaction compartment; accurate but low information; kept non-core.

Biological processes (mostly non-core / downstream)

• Immune-receptor signaling (BCR, FcεRI, FcγR, C-type lectin) — LYN executes proximal phosphorylation; treated as core-adjacent.
• DNA damage response / SAPK-JNK: "activation of SAPK by DNA damage is mediated in part by Lyn" PMID:10891478; "these two proteins physically and functionally interact to regulate DNA damage-induced apoptosis" (GADD34/PPP1R15A) PMID:11517336.
• Integrin/adhesion & chemotaxis: "in chemokine-stimulated hematopoietic cells Lyn kinase is a positive regulator of cell movement while negatively regulating adhesion to stromal cells by inhibiting the ICAM-1-binding activity of beta(2) integrins" PMID:16467205; "in SDF-1alpha-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion" PMID:18802065.
• Hematopoiesis: mast cell (SCF/KIT) proliferation PMID:11435302, eosinophil differentiation via IL-5R PMID:11823534, thrombopoietin/erythropoietin responses.
• TLR: facilitates TLR4-TLR6 heterodimerization downstream of CD36 "these data support a role for CD36-Lyn kinase interactions ... in facilitating TLR4-TLR6 heterodimerization and signal initiation" PMID:20037584; TLR9 tyrosine phosphorylation PMID:40980882.

Disease

• Gain-of-function LYN (LAVLI): "two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508, p.Q507 and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase" causing cutaneous small-vessel vasculitis + liver fibrosis. [PMID:36932076; PMID:36122175]

Curation decisions (summary)

• Core MF: GO:0004715 (and parent GO:0004713 protein tyrosine kinase activity) = ACCEPT; ATP binding, protein kinase activity, kinase activity ACCEPT (broad/correct).
• GO:0005515 protein binding (IPI, ~40 rows): REMOVE — uninformative; interactions may be real but convey no specific function (per repo policy: never MARK_AS_OVER_ANNOTATED for protein binding).
• Membrane/raft/Golgi/nucleus/cytoplasm CC: ACCEPT; Reactome-TAS cytosol and vesicle/lysosome reaction compartments = KEEP_AS_NON_CORE.
• Receptor-proximal immunoreceptor signaling processes + phosphorylation BP: ACCEPT.
• Downstream immune/hematopoietic/adhesion/DNA-damage/TLR/MAPK/differentiation processes: KEEP_AS_NON_CORE.
• Dubious rat-ortholog (GO_REF:0000107, UniProtKB:Q07014) electronic transfers to organelles/structures not supported for human LYN (mitochondrial crista/membrane, glutamatergic synapse, postsynaptic specialization, adherens junction, gamma-tubulin binding, glycosphingolipid binding, integrin alpha2-beta1 complex, PDGFR binding, enzyme/complex binding): REMOVE or KEEP_AS_NON_CORE as noted per-row.
• No NEW terms added: kinase MF and ITAM/ITIM immunoreceptor signaling are already present; participation + comparator tests give no missing supported core function.