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Showing MPRIP — M-RIP is a alias.

MPRIP

Myosin phosphatase Rho-interacting protein · UniProt Q6WCQ1

Length
1025 aa
Mass
116.5 kDa
Annotated
2026-06-10
20 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MPRIP (p116Rip/M-RIP) is a multi-domain scaffold protein that couples the actomyosin cytoskeleton to RhoA signaling and myosin light chain phosphatase (MLCP) regulation (PMID:12732640, PMID:15545284). Through its N-terminal region it binds and bundles F-actin and localizes to stress fibers and cortical microfilaments, while existing in a complex with myosin-II (PMID:12732640). Via its C-terminal coiled-coil it binds the myosin phosphatase targeting subunit MYPT1 (MBS) and directly binds myosin, thereby targeting MLCP to actin-myosin stress fibers, activating phosphatase activity toward myosin, and reducing regulatory myosin light chain phosphorylation and actomyosin contractility (PMID:15545284, PMID:15469989, PMID:16257966). MPRIP additionally acts as a GAP-like activator of RhoA GTPase activity, and its loss raises myosin phosphorylation and stress fiber formation (PMID:15545284, PMID:16257966). This scaffolding/contractility axis is regulated by upstream kinases — PKG phosphorylation strengthens the MPRIP–MYPT1 association to enhance MLCP activity and relax smooth muscle (PMID:23723008) — and supports cellular processes including cell spreading, neurite outgrowth, smooth muscle contraction, oligodendrocyte morphogenesis, and T-cell chemotaxis (PMID:15469989, PMID:22349701, PMID:32530539). In the nucleus, MPRIP binds PIP2 and nuclear F-actin, associates with the RNA Polymerase II/Nuclear Myosin 1 complex, and forms C-terminal IDR-driven phase-separated condensates; it recruits Tyr1-phosphorylated RNAPII CTD to nuclear PIP2 structures and thereby regulates RNAPII pause-release (PMID:33918018, PMID:36979361). During apoptosis, caspase-dependent cleavage generates a C-terminal fragment that retains MYPT1 and myosin binding to drive repetitive membrane blebbing (PMID:40344468).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Established MPRIP as an F-actin-binding and -bundling protein physically linked to the contractile machinery, defining its cytoskeletal anchoring role.

    Evidence F-actin co-sedimentation with Kd measurement, EM bundling, reciprocal co-IP with myosin-II, and overexpression phenotype in NIH3T3 cells

    PMID:12732640

    Open questions at the time
    • Did not define how actin binding is regulated
    • No connection yet to phosphatase or RhoA signaling
  2. 2004 High

    Showed MPRIP simultaneously activates RhoA GTPase activity and targets/activates MLCP via MYPT1 and direct myosin binding, establishing it as a dual regulator that lowers myosin phosphorylation.

    Evidence In vitro GTPase and phosphatase assays, RhoA-GTP pull-down, direct binding, and siRNA knockdown with myosin phosphorylation readout; plus C-terminal coiled-coil mapping of the MBS85/MBS130 interaction with RNAi neurite/spreading phenotypes

    PMID:15469989 PMID:15545284

    Open questions at the time
    • GAP-like activity mechanism not structurally resolved
    • Scaffolding vs catalytic contributions to MLCP activation not fully separated
  3. 2005 High

    Demonstrated in vascular smooth muscle that MPRIP targets MYPT1 to stress fibers and controls myosin phosphorylation independent of total phosphatase, MLCK, or RhoA activity, clarifying its spatial-targeting function.

    Evidence siRNA knockdown with immunofluorescence localization, MLC phosphorylation, RhoA activity, and cell morphology readouts; plus a coiled-coil oligomerization/SRF reporter study

    PMID:16243315 PMID:16257966

    Open questions at the time
    • SRF inhibition mechanism inferred from overexpression only
    • Physiological trigger for stress-fiber targeting unresolved
  4. 2008 Medium

    Placed MPRIP downstream of JNK1 as an induced gene required for cancer cell invasion, extending its role to migratory/invasive behavior.

    Evidence JNK1 siRNA with microarray profiling and M-RIP siRNA knockdown with cell invasion assay in HeLa cells

    PMID:18636174

    Open questions at the time
    • Molecular link between JNK1 and MPRIP induction undefined
    • Single cell line; invasion mechanism not dissected
  5. 2014 Medium

    Identified PKG phosphorylation of MPRIP as a regulatory input that strengthens MYPT1 binding and enhances MLCP-driven relaxation, integrating cGMP signaling with contractility control.

    Evidence PKG activation, phosphorylation and co-IP of M-RIP/MYPT1, MLCP activity, muscle contraction assays, and siRNA rescue in gastric smooth muscle

    PMID:23723008

    Open questions at the time
    • Phosphosite(s) on MPRIP not mapped
    • Single tissue/lab
  6. 2012 Medium

    Connected MPRIP to immune-cell motility through Src-dependent syntenin-1 binding required for polarized Rac-1 activation, broadening its signaling partnerships beyond RhoA/MLCP.

    Evidence Phospho-mutant and siRNA approaches, reciprocal co-IP, Rac activation, and T-cell polarization/migration assays

    PMID:22349701

    Open questions at the time
    • How MPRIP couples to Rac-1 activation mechanistically unclear
    • Single lab
  7. 2019 Medium

    Revealed a RhoA/ROCK-independent route by which MPRIP loss raises di-phosphorylated MLC via ZIPK and altered MLCP-myosin interaction, refining the contractility mechanism.

    Evidence siRNA knockdown, di-pMLC assay, ZIPK inhibition, MLCP/myosin co-IP, and collagen gel contraction in airway smooth muscle

    PMID:31347175

    Open questions at the time
    • Direct vs indirect relationship between MPRIP and ZIPK not established
    • Single lab
  8. 2020 Medium

    Linked MPRIP to oligodendrocyte differentiation via an Ermin interaction that inactivates RhoA, showing a developmental morphogenesis role.

    Evidence Ermin–MPRIP co-IP, Ermn knockout mice, RhoA activity assay, EM myelin analysis, and behavioral assays

    PMID:32530539

    Open questions at the time
    • MPRIP-specific knockout phenotype not tested
    • Mechanism of Ermin-dependent RhoA inactivation unresolved
  9. 2021 Medium

    Established an unexpected nuclear role: MPRIP binds PIP2 and nuclear F-actin, joins the RNAPII/Nuclear Myosin 1 complex, and forms IDR-driven phase-separated condensates.

    Evidence Fractionation, super-resolution imaging, RNAPII/NM1 co-IP, PIP2-binding assay, live-cell condensate imaging, and IDR deletion constructs

    PMID:33918018

    Open questions at the time
    • Functional consequence of nuclear MPRIP not yet tested by loss-of-function in this study
    • Single lab
  10. 2023 Medium

    Defined a nuclear function whereby MPRIP recruits Tyr1-phosphorylated RNAPII CTD to PIP2 structures to regulate pause-release, mechanistically linking nuclear actin to transcription.

    Evidence Super-resolution microscopy, MPRIP siRNA, RNAPII condensate quantification, Tyr1P-CTD co-IP, and N-terminal domain mapping; plus a preprint reporting LRRC8A binding at the second PH domain coupling Nox1 ROS to RhoA/MYPT1 regulation

    PMID:36945623 PMID:36979361

    Open questions at the time
    • Genome-wide transcriptional targets not defined
    • LRRC8A interaction reported only in preprint
  11. 2025 Medium

    Showed caspase cleavage of MPRIP produces a C-terminal fragment that retains MYPT1/myosin binding to drive apoptotic membrane blebbing, revealing a death-program function.

    Evidence In vitro caspase cleavage, FRET RMLC biosensor, co-IP of truncated MPRIP with MYPT1/myosin, live-cell 3D imaging, and domain truncation

    PMID:40344468

    Open questions at the time
    • Cleavage site and responsible caspase not fully mapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the cytoskeletal/contractility scaffold function and the nuclear PIP2/RNAPII condensate function are coordinated within a cell remains unknown.
  • No mechanism for partitioning MPRIP between cytoplasm and nucleus
  • No structural model of full-length MPRIP
  • Physiological relevance of nuclear function in vivo untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0003723 RNA binding 1 GO:0008092 cytoskeletal protein binding 1 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-397014 Muscle contraction 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ERMNLRRC8AMYOSIN-IIMYPT1POLR2ARHOASDCBP
Complex memberships
RNA Polymerase II/Nuclear Myosin 1 complexmyosin light chain phosphatase (MLCP) holoenzyme

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 p116Rip (MPRIP) is a filamentous actin (F-actin)-binding protein that localizes to stress fibers and cortical microfilaments via its N-terminal region (residues 1–382). It binds F-actin with Kd ~0.5 µM, bundles F-actin in vitro, and is complexed with both F-actin and myosin-II as shown by immunoprecipitation. Overexpression disrupts stress fibers and promotes dendrite-like extensions through the N-terminal actin-binding domain. F-actin co-sedimentation assay, immunoprecipitation, electron microscopy (bundling), live-cell fluorescence localization, overexpression phenotype in NIH3T3 cells The Journal of biological chemistry High 12732640
2004 p116Rip (MPRIP) activates the GTPase activity of RhoA in vitro, acting as a GAP-like regulator; overexpression in cells diminishes EGF-induced GTP-bound RhoA levels. Additionally, p116Rip activates myosin light chain phosphatase (MLCP) holoenzyme activity by binding MYPT1 (the myosin phosphatase targeting subunit) and by directly binding myosin, thereby facilitating myosin/MLCP interaction. The activation is substrate-specific (myosin). Gene silencing of p116Rip increases myosin phosphorylation and stress fiber formation. In vitro GTPase assay, RhoA-GTP pull-down in cells, in vitro phosphatase activity assay, direct binding assays, siRNA knockdown with myosin phosphorylation readout The Journal of biological chemistry High 15545284
2004 p116Rip (MPRIP) interacts directly with the C-terminal leucine zipper of the regulatory myosin-binding subunits of myosin II phosphatase (MBS85 and MBS130) through its C-terminal coiled-coil domain. RNAi knockdown of p116Rip inhibits cell spreading and neurite outgrowth without altering myosin light chain phosphorylation, indicating a scaffolding role for targeting myosin phosphatase to the actin cytoskeleton essential for RhoA/ROCK-regulated neuritogenesis. Direct binding/interaction assays, RNA interference knockdown, neurite outgrowth assay, myosin light chain phosphorylation measurement Molecular biology of the cell High 15469989
2005 M-RIP (MPRIP) targets myosin phosphatase to actin-myosin stress fibers in vascular smooth muscle cells. siRNA silencing of M-RIP reduces localization of the myosin binding subunit (MYPT1) to stress fibers and increases basal and LPA-stimulated myosin light chain phosphorylation, without changing total cellular myosin phosphatase or MLCK or RhoA activities. Silencing also increases stress fiber numbers, cell area, and reduces stress fiber inhibition by Rho-kinase inhibitor. siRNA knockdown, immunofluorescence localization, myosin light chain phosphorylation assay, RhoA activity assay, cell morphology analysis The Journal of biological chemistry High 16257966
2005 p116Rip (MPRIP) oligomerizes via its C-terminal coiled-coil domain and inhibits RhoA-mediated SRF transcription factor activation when overexpressed, without affecting RhoA-GTP levels. Mutant forms unable to oligomerize or bind MBS still inhibit SRF activity, suggesting the inhibition is mediated through disassembly of the actomyosin cytoskeleton downstream of RhoA. Overexpression of wild-type and mutant constructs, SRF reporter assay, RhoA-GTP pull-down FEBS letters Medium 16243315
2008 M-RIP (MPRIP) expression is upregulated downstream of JNK1 signaling in EGF-stimulated HeLa cells. siRNA knockdown of M-RIP significantly reduces invasive activity of cancer cells, identifying M-RIP as a JNK1 target gene required for cell invasion. JNK1 siRNA + microarray gene expression profiling, M-RIP siRNA knockdown, cell invasion assay International journal of molecular medicine Medium 18636174
2012 Syntenin-1 associates with M-RIP (MPRIP) in a manner dependent on Src-mediated phosphorylation of syntenin-1 at Tyr4. This syntenin-1/M-RIP interaction is required for polarized Rac-1 activation during T cell chemotaxis and immune synapse formation with antigen-presenting cells, controlling actin polymerization at the leading edge and contact zone. Mutant and siRNA approaches, biochemical co-immunoprecipitation, Rac activation assay, T cell polarization and migration assays, APC contact assays Journal of cell science Medium 22349701
2014 PKG (cGMP-dependent protein kinase) phosphorylates M-RIP (MPRIP) in gastric smooth muscle cells. This phosphorylation enhances M-RIP association with MYPT1 (the regulatory subunit of MLCP), augments MLCP activity, promotes MLC20 dephosphorylation, and inhibits muscle contraction downstream of Ca2+ and RhoA pathways. The effect is attenuated by M-RIP siRNA knockdown. PKG activator treatment, M-RIP siRNA knockdown, phosphorylation assay, co-immunoprecipitation of M-RIP/MYPT1, MLCP activity assay, muscle contraction assay Cell biochemistry and biophysics Medium 23723008
2019 p116Rip (MPRIP) knockdown in human airway smooth muscle cells increases di-phosphorylated MLC (Ser19 and Thr18) by altering the interaction between MLCP and myosin, not through RhoA/ROCK signaling. Zipper-interacting protein kinase (ZIPK) is involved in the increased di-phosphorylation, as ZIPK inhibition abolishes the effect. Knockdown also increases histamine-induced collagen gel contraction. siRNA knockdown, myosin phosphorylation assay (di-pMLC), ZIPK inhibition, co-immunoprecipitation of MLCP/myosin interaction, collagen gel contraction assay Journal of cellular physiology Medium 31347175
2020 Ermin (oligodendrocyte-specific protein) interacts with MPRIP/p116RIP and together they inactivate RhoA, contributing to oligodendrocyte morphogenesis and differentiation. Ermn knockout in mice causes aberrant myelin architecture and impaired motor coordination; accelerated demyelination was also observed. Co-immunoprecipitation (Ermin–MPRIP interaction), Ermn knockout mouse model, RhoA activity assay, myelin architecture analysis by EM, behavioral assays Glia Medium 32530539
2021 MPRIP is present in the cell nucleus where it binds phosphatidylinositol 4,5-bisphosphate (PIP2), localizes to nuclear speckles and nuclear lipid islets, and is a component of the RNA Polymerase II/Nuclear Myosin 1 complex. MPRIP forms phase-separated condensates that bind nuclear F-actin fibers; phase separation is driven by its C-terminal intrinsically disordered region (IDR). When F-actin is disassembled, fibrous MPRIP reforms spherical condensates, retaining liquid-like properties. Subcellular fractionation, immunofluorescence/super-resolution microscopy, co-immunoprecipitation with RNAPII/NM1, PIP2-binding assay, live-cell imaging of condensate dynamics, IDR deletion constructs Cells Medium 33918018
2023 MPRIP recruits Tyr1-phosphorylated CTD of RNAPII (Tyr1P-CTD) to nuclear PIP2-containing structures. MPRIP depletion increases the number of RNAPII initiation condensates, indicating a defect in transcription elongation/pause-release. The N-terminal domain of MPRIP (containing the F-actin binding region) mediates interaction with Tyr1P-CTD, linking nuclear F-actin to RNAPII condensation and transcription regulation. Super-resolution microscopy, siRNA depletion of MPRIP, RNAPII condensate quantification, co-immunoprecipitation of MPRIP with Tyr1P-CTD, domain mapping Biomolecules Medium 36979361
2023 LRRC8A volume-regulated anion channels physically associate with MPRIP in vascular smooth muscle cells. LRRC8A binds at the second Pleckstrin Homology (PH) domain of MPRIP. LRRC8A/MPRIP interaction connects Nox1-derived reactive oxygen species to RhoA/MYPT1/actin cytoskeletal regulation; MPRIP is a target of redox modification (sulfenylation) following TNFα exposure. siLRRC8A or LRRC8A blockade decreases RhoA activity and reduces MYPT1 T853 phosphorylation. Co-immunoprecipitation followed by mass spectrometry, confocal co-localization of tagged proteins, proximity ligation assay, IP/western blot with domain mapping, RhoA activity assay, MYPT1 phosphorylation assay, siRNA knockdown bioRxivpreprint Medium 36945623
2025 During apoptosis, MPRIP is cleaved in a caspase-dependent manner, generating a C-terminal fragment that retains interaction with MYPT1. This C-terminal fragment translocates to the cytoplasm and forms a complex with MYPT1 and myosin, promoting dephosphorylation of regulatory myosin light chain (RMLC) and driving repetitive bleb formation cycles characteristic of apoptosis. FRET-based RMLC phosphorylation biosensor, in vitro caspase cleavage assay, co-immunoprecipitation of truncated MPRIP with MYPT1/myosin, live-cell 3D membrane imaging, domain truncation analysis The FEBS journal Medium 40344468

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 p116Rip decreases myosin II phosphorylation by activating myosin light chain phosphatase and by inactivating RhoA. The Journal of biological chemistry 58 15545284
2005 M-RIP targets myosin phosphatase to stress fibers to regulate myosin light chain phosphorylation in vascular smooth muscle cells. The Journal of biological chemistry 57 16257966
2004 p116Rip targets myosin phosphatase to the actin cytoskeleton and is essential for RhoA/ROCK-regulated neuritogenesis. Molecular biology of the cell 40 15469989
2012 Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions. Journal of cell science 32 22349701
2003 p116Rip is a novel filamentous actin-binding protein. The Journal of biological chemistry 31 12732640
2015 Fusion of PDGFRB to MPRIP, CPSF6, and GOLGB1 in three patients with eosinophilia-associated myeloproliferative neoplasms. Genes, chromosomes & cancer 29 26355392
2021 The F-Actin-Binding MPRIP Forms Phase-Separated Condensates and Associates with PI(4,5)P2 and Active RNA Polymerase II in the Cell Nucleus. Cells 25 33918018
2023 PIP2-Effector Protein MPRIP Regulates RNA Polymerase II Condensation and Transcription. Biomolecules 17 36979361
2020 Ermin is a p116RIP -interacting protein promoting oligodendroglial differentiation and myelin maintenance. Glia 16 32530539
2008 M-RIP, a novel target of JNK signaling and a requirement for human cancer cell invasion. International journal of molecular medicine 13 18636174
2005 Inhibition of RhoA-mediated SRF activation by p116Rip. FEBS letters 13 16243315
2014 Inhibition of MLC20 phosphorylation downstream of Ca2+ and RhoA: A novel mechanism involving phosphorylation of myosin phosphatase interacting protein (M-RIP) by PKG and stimulation of MLC phosphatase activity. Cell biochemistry and biophysics 12 23723008
2020 Identification of a Novel MPRIP-ROS1 Fusion and Clinical Efficacy of Crizotinib in an Advanced Lung Adenocarcinoma Patient: A Case Report. OncoTargets and therapy 8 33116618
2019 p116Rip promotes myosin phosphatase activity in airway smooth muscle cells. Journal of cellular physiology 8 31347175
2023 Germline VWF/MPRIP and somatoplasm FGA variants synergically confer susceptibility to non-traumatic osteonecrosis of the femoral head. Scientific reports 2 36813871
2023 LRRC8A anion channels modulate vasodilation via association with Myosin Phosphatase Rho Interacting Protein (MPRIP). bioRxiv : the preprint server for biology 2 36945623
2025 MPRIP::PDGFRB Fusion Gene: A Rare Case Report of Adult Myeloid/Lymphoid Neoplasm With Eosinophilia and Tyrosine Kinase Gene Fusions. Case reports in hematology 1 40621131
2026 MPRIP::PDGFRB fusion identified in a male patient with a myeloid/lymphoid neoplasm with eosinophilia. Annals of hematology 0 42043473
2025 Caspase-mediated cleavage of a scaffold protein, MPRIP, yields a truncated form that is involved in repetitive bleb formation. The FEBS journal 0 40344468
2025 Remarkable response to crizotinib in a patient with advanced lung adenocarcinoma harboring the MPRIP-ROS1 fusion gene: A case report. Respiratory medicine case reports 0 40678598

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