Affinage

SHROOM2

Protein Shroom2 · UniProt Q13796

Length
1616 aa
Mass
176.4 kDa
Annotated
2026-06-10
43 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHROOM2 is an actin-associated scaffolding protein that organizes the actomyosin cytoskeleton at cortical and apical junctional sites to control epithelial and endothelial cell shape and contractility (PMID:17666436, PMID:21248203). It binds F-actin directly and protects actin filaments from depolymerization, and through distinct domains assembles a network of cytoskeletal and junctional partners: the MyTH4-FERM domain of myosin VIIa, the tight-junction protein ZO-1 via its serine/proline-rich region, and Rho-associated kinase (ROCK), which it both binds and serves as a phosphorylation substrate for (PMID:17666436, PMID:26101221). By recruiting ROCK and activated myosin II to cell-cell adhesion sites, SHROOM2 drives contractile network formation; its depletion in endothelial cells disorganizes stress fibers, reduces collagen contraction, and enhances angiogenic sprouting (PMID:21248203). SHROOM2 operates as part of a ternary SCRIB-SHROOM2-ROCK1 scaffold, with SCRIB providing a conserved SHROOM-binding site required for apical cell shape control and myosin light chain polarization during epithelial differentiation (PMID:26101221, PMID:37930352). In development, SHROOM2 governs apical positioning of melanosomes in retinal pigment epithelium in a Rab27a-dependent manner (PMID:16987870) and is required for epithelial cell elongation in the neural tube (PMID:19384856). Through its PDZ domain SHROOM2 binds the C-terminal PDZ ligand of claudin-11, and its loss in oligodendroglial cells impairs differentiation in association with altered Akt phosphorylation (PMID:40230506). Rare deleterious SHROOM2 missense variants found in neural tube defect patients disrupt its binding to ROCK1 (PMID:29423651), and an HLD22-associated claudin-11 mutation abolishes its interaction with the SHROOM2 PDZ domain (PMID:40230506).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 Low

    Establishing where SHROOM2 acts within an epithelial cell, this work placed the protein at the apical membrane and showed its distribution responds to hormonal stimulation, hinting at a role in regulated membrane trafficking.

    Evidence RT-PCR and immunocytochemistry with vasopressin stimulation in LLC-PK1 renal epithelial cells

    PMID:14982925

    Open questions at the time
    • Localization by immunocytochemistry only, not independently confirmed
    • No functional manipulation of SHROOM2
    • Link to membrane trafficking is correlative
  2. 2006 Medium

    Two studies defined SHROOM2's baseline cytoskeletal behavior and a developmental output: it localizes to cortical actin (distinct from the stress-fiber-associated Shroom) and is necessary and sufficient for apical melanosome positioning in retinal pigment epithelium.

    Evidence Transfection/imaging and chimeric targeting in fibroblasts/epithelia; morpholino knockdown, ectopic expression, and Rab27a epistasis in Xenopus

    PMID:16684770 PMID:16987870

    Open questions at the time
    • Direct binding partners mediating cortical actin localization not yet mapped
    • Mechanism linking SHROOM2 to Rab27a-dependent melanosome maturation undefined
  3. 2007 High

    This work built the molecular interaction map underlying SHROOM2 scaffolding by demonstrating direct binding to myosin VIIa, F-actin, and ZO-1, anchoring the protein to both the actin cytoskeleton and tight junctions.

    Evidence Yeast two-hybrid, in vitro binding, reciprocal Co-IP from brain/cochlear tissue, actin-protection assay in MDCK cells

    PMID:17666436

    Open questions at the time
    • Functional consequence of the myosin VIIa interaction not tested in vivo
    • Domain on SHROOM2 binding myosin VIIa not finely mapped
  4. 2009 Medium

    Connecting SHROOM2 to tissue morphogenesis, this study showed it is both required and sufficient for epithelial cell elongation in the neural tube.

    Evidence Morpholino knockdown, ectopic expression, and cell-height measurement in Xenopus neural epithelium

    PMID:19384856

    Open questions at the time
    • Molecular effectors downstream of SHROOM2 in cell elongation not identified
    • Single-organism/single-lab evidence
  5. 2010 Medium

    This work tied SHROOM2 to dynamic apical shape remodeling by showing transient co-accumulation with F-actin, myosin VIIa, and myosin II at the developing apical junctional complex of cochlear hair cells.

    Evidence Immunostaining and geometric analysis of the apical junctional complex across mouse cochlear mutant backgrounds

    PMID:20332152

    Open questions at the time
    • No functional manipulation of SHROOM2 in this system
    • Causal role in apical remodeling inferred from localization only
  6. 2011 High

    This study mechanistically linked SHROOM2 to contractility by showing it directly binds ROCK and is required to recruit ROCK and active myosin II to cell-cell adhesions, controlling endothelial contractile network formation and angiogenic sprouting.

    Evidence siRNA in HUVECs and ES-cell-derived endothelium, collagen contraction, sprouting assays, ROCK/pMLC immunofluorescence, direct interaction assay

    PMID:21248203

    Open questions at the time
    • Whether ROCK recruitment depends on the same domains binding actin/ZO-1 not resolved
    • In vivo angiogenesis role not directly tested
  7. 2015 Medium

    This work refined the SHROOM2-ROCK relationship by identifying SHROOM2 as a ROCK2 phosphorylation substrate and showing it assembles a phosphorylation-dependent ternary complex with Rho-kinase and Scrib that controls subcellular contractility.

    Evidence Kinase-interacting substrate screening (KISS) and Co-IP of the ternary complex

    PMID:26101221

    Open questions at the time
    • Specific SHROOM2 phosphosites and their functional effect not defined
    • Stoichiometry and assembly order of the ternary complex unknown
  8. 2016 Medium

    By dissecting ZO-1 domain interactions in lumen formation, this study confirmed the ZO-1/SHROOM2 interaction but showed SHROOM2, unlike occludin, is dispensable for single-lumen formation, delimiting the contexts where the interaction is functionally required.

    Evidence ZO-1 domain-deletion mutants and partner-specific siRNA in 3D MDCK cyst culture

    PMID:27802160

    Open questions at the time
    • Functional role of the ZO-1/SHROOM2 interaction in other epithelial contexts not addressed
    • Negative result does not exclude redundancy
  9. 2018 Medium

    This work linked SHROOM2 to human disease by showing neural-tube-defect patient missense variants disrupt SHROOM2 binding to ROCK1, connecting the ROCK-scaffolding function to a pathological phenotype.

    Evidence Targeted sequencing of patients plus mammalian two-hybrid and western blot of mutant versus wild-type SHROOM2

    PMID:29423651

    Open questions at the time
    • Causality of variants for NTD not established beyond interaction disruption
    • Cellular/developmental consequence of binding loss not shown
  10. 2019 Medium

    This study distinguished SHROOM2's roles in cancer, showing it contributes to RhoA-ROCK stress-fiber formation yet restrains EMT and invasion through a ROCK-independent mechanism, indicating SHROOM2 functions beyond simple ROCK epistasis.

    Evidence siRNA, Y-27632 ROCK inhibition, migration/invasion and EMT-marker assays in nasopharyngeal carcinoma cells

    PMID:30683844

    Open questions at the time
    • The ROCK-independent effector restraining EMT not identified
    • In vivo tumor relevance not established
  11. 2023 Medium

    This work established SCRIB as the scaffold organizing SHROOM2/4 and ROCK1, mapping a conserved SHROOM-binding site in SCRIB required for apical cell shape and myosin light chain polarization during epithelial differentiation.

    Evidence SCRIB KO and SHROOM-binding-site mutagenesis in organ-on-chip gut epithelium with Co-IP and myosin light chain immunofluorescence

    PMID:37930352

    Open questions at the time
    • Relative contributions of SHROOM2 versus SHROOM4 not separated
    • How SCRIB scaffolding integrates with the ZO-1/myosin VIIa interactions unknown
  12. 2025 Medium

    This study extended SHROOM2 scaffolding into glial biology, showing its PDZ domain binds the claudin-11 PDZ ligand and that SHROOM2 loss impairs oligodendroglial differentiation via altered Akt phosphorylation, with a disease mutation abolishing the interaction.

    Evidence Co-IP, PDZ domain/ligand transfection, siRNA, and western blot for differentiation markers and Akt phosphorylation in FBD-102b cells

    PMID:40230506

    Open questions at the time
    • Mechanism connecting SHROOM2/claudin-11 to Akt signaling undefined
    • In vivo relevance to HLD22 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHROOM2's multiple interactions (actin, myosin VIIa, ZO-1, ROCK, SCRIB, claudin-11) are coordinated in space and time, and which are required for each tissue-specific output, remains unresolved.
  • No integrated structural model of SHROOM2 domain usage
  • Tissue-specific partner requirements not systematically dissected
  • Phosphorylation regulation of complex assembly incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
CLDN11MYO7AROCK1ROCK2SCRIBTJP1
Complex memberships
SCRIB-SHROOM2-ROCK1 ternary complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SHROOM2 directly interacts with the C-terminal MyTH4-FERM domain of myosin VIIa via yeast two-hybrid and binds F-actin; a SHROOM2 fragment containing the F-actin interaction region protects actin filaments from cytochalasin-D-induced disruption in MDCK cells. SHROOM2 also directly interacts with ZO-1 (TJP1) via its serine- and proline-rich region in vitro, and the two proteins co-immunoprecipitate from brain and cochlear extracts and co-localize at tight junctions. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation from tissue extracts, transfection/localization in MDCK and LE cells, cytochalasin-D protection assay Journal of cell science High 17666436
2006 SHROOM2 (APXL) is necessary and sufficient to govern localization of pigment granules (melanosomes) at the apical surface of retinal pigment epithelium cells in Xenopus. Loss of Shroom2 causes failure of melanosome maturation and apical association; ectopic expression in naive epithelial cells drives apical pigment accumulation in a manner requiring Rab27a GTPase. Additionally, Shroom2 induces apical accumulation of gamma-tubulin at apical cell surfaces. Morpholino knockdown in Xenopus embryos, ectopic expression, epistasis with Rab27a dominant-negative/knockdown, immunostaining Development (Cambridge, England) High 16987870
2006 SHROOM2 (Apxl) localizes to cortical actin in fibroblasts (unlike Shroom which associates with stress fibers). In epithelial cells, Apxl does not induce apical constriction as Shroom does, but acquires this capacity when artificially targeted to the apical junctional complex. SHROOM2 regulates cytoskeletal organization and architecture of endothelial cells. Transfection and fluorescence microscopy in fibroblasts and epithelial cells, chimeric protein targeting experiments The Journal of biological chemistry Medium 16684770
2011 SHROOM2 directly interacts with Rho kinase (ROCK) and facilitates the formation of a contractile network within endothelial cells. Depletion of Shrm2 results in decreased stress fiber organization, reduced collagen contraction, loss of ROCK and activated myosin II from cell-cell adhesion sites, and elevated branching/sprouting angiogenic behavior. This phenotype is recapitulated in HUVECs and embryonic stem cell-derived vasculogenesis assays. siRNA knockdown in HUVECs and ES cell-derived endothelial cells, collagen contraction assay, immunofluorescence for ROCK/pMLC, tube/sprouting angiogenesis assay, direct interaction assay with ROCK Molecular biology of the cell High 21248203
2009 In Xenopus, ectopic expression of Shroom2 increases epithelial cell height and loss of Shroom2 function results in failure of cell elongation in the neural epithelium, demonstrating Shroom2 is required for epithelial cell morphology in the neural tube. In situ hybridization for expression, morpholino knockdown (loss-of-function), ectopic expression in Xenopus embryos, cell height measurements Developmental dynamics Medium 19384856
2015 SHROOM2 is identified as a candidate phosphorylation substrate for Rho-associated kinase (ROCK2) by the KISS method. SHROOM2 assembles into a ternary complex with Rho-kinase and Scrib in a phosphorylation-dependent manner, and this complex plays a crucial role in regulation of subcellular contractility. Kinase-interacting substrate screening (KISS), co-immunoprecipitation of ternary complex, phosphorylation-dependent interaction assays The Journal of cell biology Medium 26101221
2019 SHROOM2 participates in RhoA-ROCK-induced stress fiber formation and focal adhesion in nasopharyngeal carcinoma cells. Depletion of SHROOM2 also drives epithelial-to-mesenchymal transition (EMT) and enhances cell migration/invasion through a ROCK-independent mechanism; ROCK inhibitor Y-27632 did not cause EMT, and combined ROCK inhibition plus SHROOM2 depletion produced greater migration/invasion than either alone, indicating a synergistic rather than epistatic relationship. siRNA knockdown in NPC cells, ROCK inhibitor (Y-27632) treatment, wound-healing/invasion assays, immunofluorescence for EMT markers and stress fibers, clinical sample analysis Cell death & disease Medium 30683844
2018 Rare deleterious missense variants in SHROOM2 (p.A1331S; p.R1557H) found in neural tube defect patients disrupt SHROOM2 binding to ROCK1 in vitro, as confirmed by mammalian two-hybrid assay and western blot. Targeted next-generation sequencing, Sanger sequencing confirmation, mammalian two-hybrid assay, western blot Human genetics Medium 29423651
2016 ZO-1's U5-GuK domain binds shroom2 (among other partners), and the ZO-1/occludin interaction (via the OCEL domain) but not the shroom2 interaction is required for single lumen formation in 3D epithelial culture; deletion of shroom2 alone did not lead to multi-lumen cysts, distinguishing it from occludin's role. ZO-1 domain-deletion mutants in 3D MDCK cyst culture, siRNA knockdown of binding partners including shroom2, immunofluorescence for lumen number and spindle orientation Journal of cell science Medium 27802160
2010 During cochlear outer hair cell apical circumference remodeling in mice, SHROOM2 and F-actin transiently accumulate in the developing lateral lobes of the apical junctional complex, concurrent with polarized redistribution of myosin VIIa and myosin II, implicating SHROOM2 in actomyosin cytoskeleton-mediated apical shape remodeling. Immunostaining and geometric analysis of AJC in mouse cochlea (wild-type and hair bundle morphogenesis mutants), comparison across mutant backgrounds Development (Cambridge, England) Medium 20332152
2023 SCRIB serves as a molecular scaffold for SHROOM2/4 and ROCK1 during epithelial differentiation; SCRIB contains an evolutionarily conserved SHROOM-binding site in its C-terminus required for SCRIB function in controlling apical cell shape and apical contractility. SCRIB KO gut-like epithelia are flatter with reduced apical surface area and defective myosin light chain polarization. SCRIB KO in organ-on-chip gut epithelium model, site-directed mutagenesis of SHROOM-binding site in SCRIB, co-immunoprecipitation, immunofluorescence for myosin light chain, evolutionary conservation analysis The Journal of cell biology Medium 37930352
2004 ApxL (SHROOM2) protein is expressed in LLC-PK1 renal epithelial cells and localizes to both the apical membrane and cytoplasmic compartments; vasopressin stimulation modifies ApxL cellular distribution, consistent with increased membrane-associated ApxL, suggesting a role in regulated membrane trafficking in the proximal nephron. RT-PCR, immunocytochemistry, vasopressin stimulation experiment in LLC-PK1 cells The Journal of biological chemistry Low 14982925
2025 Claudin-11 (an HLD22-associated protein) directly interacts with SHROOM2 via its C-terminal PDZ ligand sequence binding to SHROOM2's PDZ domain. Knockdown of SHROOM2 in FBD-102b oligodendroglial cells reduces morphological differentiation and marker protein expression; this is linked to altered phosphorylation of Akt kinase. An HLD22-associated claudin-11 mutation abolishes its interaction with the SHROOM2 PDZ domain. Co-immunoprecipitation, siRNA knockdown, transfection of PDZ domain/ligand sequences, western blot for differentiation markers and Akt phosphorylation, morphological analysis BBA advances Medium 40230506

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Regulation of pea cytosolic ascorbate peroxidase and other antioxidant enzymes during the progression of drought stress and following recovery from drought. The Plant journal : for cell and molecular biology 213 8180623
2016 ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture. Journal of cell science 108 27802160
2012 A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer's disease in the ADNI cohort. NeuroImage 94 22245343
2015 Kinase-interacting substrate screening is a novel method to identify kinase substrates. The Journal of cell biology 69 26101221
2014 Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis. Carcinogenesis 62 24760461
2007 Shroom2, a myosin-VIIa- and actin-binding protein, directly interacts with ZO-1 at tight junctions. Journal of cell science 60 17666436
2006 Differential actin-dependent localization modulates the evolutionarily conserved activity of Shroom family proteins. The Journal of biological chemistry 58 16684770
2018 Differences in MWCNT- and SWCNT-induced DNA methylation alterations in association with the nuclear deposition. Particle and fibre toxicology 50 29426343
2014 A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 49 25473003
2013 STAT3 expression, activity and functional consequences of STAT3 inhibition in esophageal squamous cell carcinomas and Barrett's adenocarcinomas. Oncogene 48 23912451
2009 The shroom family proteins play broad roles in the morphogenesis of thickened epithelial sheets. Developmental dynamics : an official publication of the American Association of Anatomists 48 19384856
2011 Shroom2 regulates contractility to control endothelial morphogenesis. Molecular biology of the cell 44 21248203
2004 Heterogeneous patterns of variation among multiple human x-linked Loci: the possible role of diversity-reducing selection in non-africans. Genetics 43 15342522
2010 Cochlear outer hair cells undergo an apical circumference remodeling constrained by the hair bundle shape. Development (Cambridge, England) 41 20332152
2006 Shroom2 (APXL) regulates melanosome biogenesis and localization in the retinal pigment epithelium. Development (Cambridge, England) 40 16987870
2019 SHROOM2 inhibits tumor metastasis through RhoA-ROCK pathway-dependent and -independent mechanisms in nasopharyngeal carcinoma. Cell death & disease 34 30683844
1995 Cloning of a human homologue of the Xenopus laevis APX gene from the ocular albinism type 1 critical region. Human molecular genetics 34 7795590
2006 A new standard nomenclature for proteins related to Apx and Shroom. BMC cell biology 33 16615870
2020 Transcriptome-based screening of intracellular pathways and angiogenesis related genes at different stages of thiram induced tibial lesions in broiler chickens. BMC genomics 24 31941444
2004 Identification of DNA copy number changes in microdissected serous ovarian cancer tissue using a cDNA microarray platform. Cancer genetics and cytogenetics 24 15571795
2008 Tackling the characterization of canine chromosomal breakpoints with an integrated in-situ/in-silico approach: the canine PAR and PAB. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 21 19005636
2018 Genetic and functional analysis of SHROOM1-4 in a Chinese neural tube defect cohort. Human genetics 19 29423651
2022 Genome-wide, evolutionary, and functional analyses of ascorbate peroxidase (APX) family in Poaceae species. Genetics and molecular biology 17 36512713
2021 Ascorbate Peroxidase Neofunctionalization at the Origin of APX-R and APX-L: Evidence from Basal Archaeplastida. Antioxidants (Basel, Switzerland) 17 33924520
1996 A new region of conservation is defined between human and mouse X chromosomes. Genomics 16 8661129
2021 MicroRNAs in amniotic fluid and maternal blood plasma associated with sex determination and early gonad differentiation in cattle†. Biology of reproduction 12 33889937
2022 The Implication of X-Linked Genetic Polymorphisms in Susceptibility and Sexual Dimorphism of Cancer. Anticancer research 11 35489753
2018 Comprehensive inbred variation discovery in Bama pigs using de novo assemblies. Gene 10 30179680
2004 Characterization of Na+-permeable cation channels in LLC-PK1 renal epithelial cells. The Journal of biological chemistry 9 14982925
2023 Uncovering the candidate genes related to sheep body weight using multi-trait genome-wide association analysis. Frontiers in veterinary science 7 37662987
2023 SCRIB controls apical contractility during epithelial differentiation. The Journal of cell biology 7 37930352
2014 Congenital nasal pyriform aperture stenosis and ocular albinism co-occurring in a sibship with a maternally-inherited 97 kb Xp22.2 microdeletion. American journal of medical genetics. Part A 7 24478262
2018 Ocular albinism with infertility and late-onset sensorineural hearing loss. American journal of medical genetics. Part A 6 30160833
1998 An integrated genetic and man-mouse comparative map of the DXHXS674-Pdha1 region of the mouse X chromosome. Genomics 6 9503026
2025 Genetic differences between primary colorectal cancer and its paired synchronous and metachronous metastases. International journal of cancer 4 40884237
2021 An 8.22 Mb Assembly and Annotation of the Alpaca (Vicugna pacos) Y Chromosome. Genes 4 33467186
2024 Clinical and Genetic Analysis of Multiple Idiopathic Cervical Root Resorption. The Chinese journal of dental research 3 38546524
2024 Novel mutation leading to splice donor loss in a conserved site of DMD gene causes Duchenne muscular dystrophy with cryptorchidism. Journal of medical genetics 3 38621993
2025 Regulatory role of lnc-MAP3K13-3:1 on miR-6894-3p and SHROOM2 in modulating cellular dynamics in hepatocellular carcinoma. BMC cancer 2 39810131
2025 Claudin-11, a hypomyelinating leukodystrophy 22 (HLD22)-responsible protein, uniquely interacts with shroom-2 to change cell phenotypes. BBA advances 1 40230506
2026 Exome-Wide Association Analysis Identifies Rare Germline Susceptibility Variants in Early-Onset Breast Cancer Among Saudi Women. International journal of molecular sciences 0 41751868
2026 Integrative phosphoproteomic analysis reveals co-regulatory phosphorylation networks of rhotekin in cancer progression. Discover oncology 0 41963591
2025 An investigation of a hemophilia A female with heterozygous intron 22 inversion and skewed X chromosome inactivation. Frontiers in genetics 0 39834547

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