TGF-β/Smad signaling · target hub

LRRC15

TGF-β–induced · CAF / stromal transmembrane protein

Leucine-rich repeat-containing protein 15 (LRRC15; also LIB / hLib)

LRRC15 is a TGF-β–strongly induced type I transmembrane LRR protein enriched on cancer-associated fibroblasts (CAFs) and some mesenchymal-like cancer cells. It marks TGF-β–driven stromal programs and links to immune suppression, fibrosis, and poor immunotherapy response. Downstream it can couple to ITGB1/FAK → PI3K/AKT(/mTOR), but its primary pathway home is the TGF-β/Smad axis—not a core PI3K kinase node.

Back to pathway overviewSearch: LRRC15UniProt (Q8TF66)Downstream: PI3K/Akt/mTOR

Research notes

  • Induction: TGF-β upregulates LRRC15 via SMAD2/3-dependent transcription—a common readout of TGF-β–active stroma (e.g. PubMed:39651139).
  • Context: Enriched on CAFs / myofibroblast-like stroma and some mesenchymal tumor cells; limited expression in many normal adult tissues.
  • Function: Linked to ECM remodeling and immunosuppressive TME; depleting LRRC15⁺ CAFs can improve CD8⁺ T-cell infiltration (model-dependent).
  • Downstream: Can engage ITGB1 and promote FAK/PI3K/AKT phosphorylation, supporting proliferation and invasion (e.g. TNBC literature).
  • Antibodies: Commercial Abs often target N-terminal / LRR (e.g. CST #50546); juxta-membrane stalk (~aa 446–538, HPA035503 PrEST window) is a differentiation epitope.

On the pathway hub (sections)

Genetics & expression context (quick reference)

Type / exampleDomain / context (brief)
Expression (CAF / stroma)TGF-β–induced; high in tumor stroma, limited in many normal tissues
V264I (rs13060627)UniProt natural variant VAR_051101; validate function case-by-case
P286L (rs13070515)UniProt natural variant VAR_051102; validate function case-by-case
Isoform 2Alternative isoform in UniProt—confirm isoform in assays

Driver mutations are uncommon; clinical interest is mostly expression as a CAF / TGF-β program marker and ADC / TME work. Annotate variants with ClinVar / COSMIC / primary papers.

Assay readouts for LRRC15

  • Protein: WB / IHC / IF / flow for total LRRC15; pair with TGF-β time courses and ALK5 inhibitors (e.g. SB431542).
  • Transcript: qPCR / RNA-seq of LRRC15 with CAF panels (ACTA2, COL1A1, FAP).
  • Upstream: p-SMAD2/3 and total SMAD2/3; nuclear/cytoplasmic distribution.
  • Downstream crosstalk (optional): p-FAK (Tyr397), p-AKT (Ser473), p-PI3K with ITGB1/FAK perturbations.
  • Phenotypes: collagen deposition, migration/invasion, T-cell infiltration in co-culture (project-dependent).
  • Epitopes: check whether the immunogen maps to LRR vs juxta-membrane stalk (HPA035503 ≈ aa 446–540).

LRRC15 experimental notes (selected)

Induction assays often use recombinant TGF-β1 on serum-starved fibroblasts / CAFs; block with ALK5 inhibitors. Expect upward MW shifts from N-glycosylation on WB.

Common cell / model contexts

  • Primary CAFs / fibroblasts (TGF-β induction)
  • TNBC / mesenchymal-like tumor lines (expression-dependent)
  • Murine work: confirm species Ab cross-reactivity

WB lysate tips

  • Reducing SDS-PAGE; expect > predicted ~65 kDa (glycosylation)
  • PNGase F shift confirms N-glycans
  • TGF-β 24–48 h often peaks induction (system-dependent)

Tissue / IHC tips

  • Tumor stroma / CAF localization; pair with α-SMA / FAP
  • Include low-expression normal-tissue controls
  • FFPE clone choice per vendor validation

IP / interaction tips

  • ITGB1 / FAK co-IP (as in literature systems)
  • Surface protein: gentle lysis ± crosslinking (optional)
  • MS of glycopeptides needs enrichment strategy

Cell-line and tissue performance vary by clone and fixation—validate against datasheets and papers.

Protein reference

Conservation · sequence · PTMs (PIK3C3-style)

Species conservation (vs human Q8TF66)

SpeciesUniProtLengthIdentity
HumanQ8TF66581
100%
MouseQ80X72579
72%
RatQ8R5M3578
72%

Identity is an approximate pairwise estimate vs human (best offset, ungapped)—for Ab/peptide species guidance only; use BLAST / Clustal for precise alignments. Swiss-Prot currently lists curated human / mouse / rat entries primarily.

Human protein sequence (UniProt)

Homo sapiensQ8TF66581 aa

Domain map (UniProt)

A75A369
  • LRRNT 22–53
  • LRR repeats 54–411
  • LRRCT 423–475
  • Key loops / regions
  • PTM sites (dot / chip → table)
        10        20        30        40        50        60
MPLKHYLLLLVGCQAWGAGLAYHGCPSECTCSRASQVECTGARIVAVPTPLPWNAMSLQI
        70        80        90       100       110       120
LNTHITELNESPFLNISALIALRIEKNELSRITPGAFRNLGSLRYLSLANNKLQVLPIGL
       130       140       150       160       170       180
FQGLDSLESLLLSSNQLLQIQPAHFSQCSNLKELQLHGNHLEYIPDGAFDHLVGLTKLNL
       190       200       210       220       230       240
GKNSLTHISPRVFQHLGNLQVLRLYENRLTDIPMGTFDGLVNLQELALQQNQIGLLSPGL
       250       260       270       280       290       300
FHNNHNLQRLYLSNNHISQLPPSVFMQLPQLNRLTLFGNSLKELSPGIFGPMPNLRELWL
       310       320       330       340       350       360
YDNHISSLPDNVFSNLRQLQVLILSRNQISFISPGAFNGLTELRELSLHTNALQDLDGNV
       370       380       390       400       410       420
FRMLANLQNISLQNNRLRQLPGNIFANVNGLMAIQLQNNQLENLPLGIFDHLGKLCELRL
       430       440       450       460       470       480
YDNPWRCDSDILPLRNWLLLNQPRLGTDTVPVCFSPANVRGQSLIIINVNVAVPSVHVPE
       490       500       510       520       530       540
VPSYPETPWYPDTPSYPDTTSVSSTTELTSPVEDYTDLTTIQVTDDRSVWGMTQAQSGLA
       550       560       570       580 
IAAIVIGIVALACSLAACVGCCCCKKRSQAVLMQMKAPNEC

Canonical isoform 1: N-terminal signal (~1–21), extracellular LRRs, juxta-membrane stalk, TM helix, and short cytoplasmic tail. Confirm isoform numbering before epitope mapping.

Post-translational modifications & related sites

SiteModificationNotes
Other modifications4
Asn75N-linked glycosylation

UniProt-curated; within LRR region—can affect apparent MW and Ab recognition.

Detection: PNGase F shift WB; lectin blot; glycoproteomics / LC-MS.

Asn369N-linked glycosylation

UniProt-curated; toward the C-terminal end of the LRR array.

Detection: Same as Asn75: PNGase F / lectin / MS.

Signal peptide (1–21)Signal peptide cleavage

Mature chain starts ~aa 22 (UniProt)—extracellular domain start.

Stalk aa 446–538Structural region (not a PTM)

Pro/Ser/Thr-rich juxta-TM stalk; HPA035503 PrEST window—used for linear epitopes more than phospho hotspots.

Detection: Peptide ELISA / polyclonal antisera; total-protein WB/IHC.

UniProt curates N75 and N369 N-glycosylation; phospho sites are less catalogued than kinase nodes—see PhosphoSitePlus / dbPTM for HTP. Natural variants are listed under genetics.

Bypass, links & crosstalk

Models & genetics note

Mouse Lrrc15 (Q80X72) is ~72% identical to human; validate Ab/peptide species cross-reactivity. CAF depletion or TGF-β blockade in vivo requires institutional ethics and proper controls.

Quick search presets

LRRC15LIB / hLibTGF-β + LRRC15CAF LRRC15SMAD2SMAD3ITGB1FAP

LRRC15-related antibodies (keyword-biased)

Adds LRRC15 keyword bias atop the TGF-β/Smad antibody pool—if sparse, use presets above or global search.

Neighboring targets (same hub)

TGFB1TGFBR1SMAD2SMAD3FAPACTA2COL1A1ITGB1

External databases

FAQ

Disclaimer & review

This content supports research reagents and pathway education—not medical advice. Validate expression, antibody clones, drug/ADC indications, and protocols with authoritative databases, datasheets, and institutional oversight.

Last reviewed: 2026-09-04