Multi-directional function of the protein phosphatase 1 regulatory subunit TIMAP

Shopik, Micheal J.; Li, Laiji; Luu, Hue-Anh; Obeidat, Marya; Holmes, Charles F.B.; Ballermann, Barbara J.

doi:10.1016/j.bbrc.2013.05.012

Cited by 14 publications

(17 citation statements)

References 30 publications

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“…TIMAP is a member of the MYPT family of PP1c-targeting subunits (33,48). The question therefore arises whether the effects of TIMAP silencing observed here can be attributed to reduced TIMAP/PP1c phosphatase activity.…”

Section: Discussionmentioning

confidence: 91%

“…TIMAP is also highly enriched in proliferating EC in culture, where it localizes to the plasma membrane in EC projections (9). Based on its amino acid sequence and on structural modeling, TIMAP is a protein phosphatase 1 (PP1c)-regulatory subunit in the myosin phosphatase-targeting subunit (MYPT) family (9,22,48). The C-terminal CAAX motif of TIMAP is modified by prenylation, leading to plasma membrane association (9,30).…”

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confidence: 99%

“…The C-terminal CAAX motif of TIMAP is modified by prenylation, leading to plasma membrane association (9,30). In EC, TIMAP interacts directly with the non-integrin laminin receptor (LAMR1) and regulates its phosphorylation (30,48). The LAMR1 is upregulated during EC proliferation and angiogenesis (35,50) and is required for capillary formation in vitro and angiogenesis in vivo (18,31).…”

mentioning

confidence: 99%

“…The LAMR1 is upregulated during EC proliferation and angiogenesis (35,50) and is required for capillary formation in vitro and angiogenesis in vivo (18,31). TIMAP also regulates moesin phosphorylation in EC (11) and can dephosphorylate MLC2 in vitro (48), but its actual mechanism of action in EC is poorly understood.…”

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confidence: 99%

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TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

Obeidat

Ballermann

2014

American Journal of Physiology-Renal Physiology

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Obeidat M, Li L, Ballermann BJ. TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells. Am J Physiol Renal Physiol 307: F623-F633, 2014. First published July 9, 2014 doi:10.1152/ajprenal.00070.2014.-The function of TIMAP, an endothelial cell (EC)-predominant protein phosphatase 1-regulatory subunit, is poorly understood. We explored the potential role of TIMAP in the Akt-dependent regulation of glomerular EC proliferation, survival, and in vitro angiogenesis. To deplete TIMAP, the EC were transfected with TIMAP-specific or nonspecific small interfering (si) RNA. The rate of electrical impedance development across subconfluent EC monolayers, a measure of the time-dependent increase in EC number, was 93 Ϯ 2% lower in TIMAP-depleted than in control EC. This effect on cell proliferation was associated with reduced DNA synthesis and increased apoptosis: TIMAP silencing reduced 5-ethynyl-2=-deoxyuridine incorporation by 38 Ϯ 2% during the exponential phase of EC proliferation, and cleaved caspase 3 as well as caspase 3 activity increased in TIMAPdepleted relative to control cells. Furthermore, TIMAP depletion inhibited the formation of angiogenic sprouts by glomerular EC in three-dimensional culture. TIMAP depletion strongly diminished growth factor-stimulated Akt phosphorylation without altering ERK1/2 phosphorylation, suggesting a specific effect on the PI3K/ Akt/PTEN pathway. Endogenous TIMAP and PTEN colocalized in EC and coimmunoprecipitated from EC lysates. The inhibitory PTEN phosphorylation on S370 was significantly reduced in TIMAP-depleted compared with control EC, while phosphorylation of PTEN on the S380/T382/T383 cluster remained unchanged. Finally, the PTEN inhibitor bpV(phen) fully reversed the suppressive effect of TIMAP depletion on Akt phosphorylation. The data indicate that in growing EC, TIMAP is necessary for Akt-dependent EC proliferation, survival, and angiogenic sprout formation and that this effect of TIMAP is mediated by inhibition of the tumor suppressor PTEN. endothelial cells; PTEN; protein phosphatase 1-regulatory subunit; PPP1R16B; apoptosis; clectric cell-substrate impedance sensing MECHANISMS THAT REGULATE ANGIOGENESIS have received massive attention since Folkman (15) first advanced the theory that tumor growth depends on new blood vessel formation. Angiogenesis involves the sprouting and elongation of new blood vessels from preexisting vessels followed by stabilization and vessel specification (28). This process is crucial for normal blood vessel formation and patterning during embryonic development, for postembryonic blood vessel repair (5), and remodeling in response to hypoxia, in the female reproductive cycle, and for the establishment of the placental vasculature. Pathological retinal and tumor vascularization also depend on angiogenesis. While endothelial cells (EC) at the tip of the angiogenic sprout determine the direction and pattern of new blood vessel growth, elongation of the new vessel stalk requires EC proliferatio...

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

Obeidat

Ballermann

2014

American Journal of Physiology-Renal Physiology

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“…Beside the structural features, several data support the PP1 regulatory subunit distinction for TIMAP. Like MYPT1, TIMAP seems to prefer binding the β (aka δ) isoform of PP1c, but in vitro results of the Ballermann's group claim the possibility of TIMAP complexes with other PP1c isoforms as well . Still, the high similarity of the catalytic subunits and their broad in vitro substrate specificities may rather call for a firm regulation of PP1 holoenzymes through restricted PP1c isoform‐regulatory/targeting subunit–substrate protein complexes (for review see Ref.…”

Section: Regulatory Subunit Of Pp1mentioning

confidence: 99%

TIMAP, the versatile protein phosphatase 1 regulator in endothelial cells

Boratkó

Csortos

2017

IUBMB Life

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Transforming growth factor (TGF)-β inhibited membrane associated protein, TIMAP, is the member of the myosin phosphatase targeting protein (MYPT) family of protein phosphatase 1 (PP1) regulatory subunits. The N-terminal part of TIMAP has a typical MYPT family structure with a sequence element called MyPhone (myosin phosphatase N-terminal element), a putative bipartite nuclear localization signal, a PP1 catalytic subunit binding motif, and five ankyrin repeats. The C-terminal half of TIMAP is intrinsically disordered, but ends with a functional CAAX box for lipid modification which allows localization of TIMAP at the plasma membrane. TIMAP is prenylated by farnesyl transferase with the contribution of the anchoring protein, RACK1 in the cytoplasm. The controlling effect of TIMAP on PP1 is moderated by PKA/GSK3β and PKC mediated phosphorylation of TIMAP, the sites are located in the disordered region of the protein. TIMAP is abundant in endothelial cells. A growing body of evidence attained through characterization of newly identified protein partners calls attention to its critical role in normal and pathological activities of the endothelium via regulation of PP1. TIMAP binds the non-integrin laminin receptor 1 and the endothelin converting enzyme 1, which may connect TIMAP to angiogenesis, tumor invasion and metastasis. Barrier protecting role of TIMAP was shown for pulmonary artery endothelial cells. ERM (ezrin-radixin-moesin) proteins, as potential in vivo PP1-TIMAP substrates, are critical targets in the barrier maintenance. TIMAP affects phosphorylation level and subcellular localization of merlin and eukaryotic elongation factor-1A1. Merlin is a key component of signaling pathways regulating cell proliferation, membrane domain formation and cell-cell junction organization. Noncanonical functions of the elongation factor include a role in organization of cytoskeleton dynamics and in apoptosis. The interacting/binding partners identified so far demonstrate a rather complex role of TIMAP in key functions of the endothelium offering TIMAP as a plausible target in pathological issues. © 2017 IUBMB Life, 69(12):918-928, 2017.

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TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis

Yang

Yin

et al. 2016

J Mol Med

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Multi-directional function of the protein phosphatase 1 regulatory subunit TIMAP

Cited by 14 publications

References 30 publications

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

TIMAP, the versatile protein phosphatase 1 regulator in endothelial cells

TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis

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