The Phosphorylation State of Threonine-220, a Uniquely Phosphatase-Sensitive Protein Kinase A Site in Microtubule-Associated Protein MAP2c, Regulates Microtubule Binding and Stability

Alexa, Anita; Schmidt, Gregor W.; Tompa, Péter; Ogueta, Samuel; Vázquez, Jesús; Kulcsár, Péter István; Kovács, János; Dombrádi, Viktor; Friedrich, Péter

doi:10.1021/bi025916s

Cited by 21 publications

(10 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data indicate that cAMP elevation and PKA activation exerts a barrier‐protective effect on TGF‐β1‐stimulated EC monolayers, which is associated with reduction of TGF‐β1‐induced Rho activation and MT stabilization. A critical role for PKA in inhibition of Rho activity (Lang et al, 1996) and MT dynamics (Alexa et al, 2002; Harada et al, 2002; Birukova et al, 2004b) has been previously described. We have recently demonstrated a leading role of Rho‐dependent mechanism in endothelial barrier compromise induced by MT disassembly and described a PKA‐dependent mechanism of EC barrier protection (Verin et al, 2001; Birukova et al, 2004b,d).…”

Section: Discussionmentioning

confidence: 98%

Involvement of microtubules and Rho pathway in TGF‐β1‐induced lung vascular barrier dysfunction

Birukova¹,

Birukov²,

Adyshev³

et al. 2005

Journal Cellular Physiology

109

116

View full text Add to dashboard Cite

Transforming growth factor-beta1 (TGF-beta1) is a cytokine critically involved in acute lung injury and endothelial cell (EC) barrier dysfunction. We have studied TGF-beta1-mediated signaling pathways and examined a role of microtubule (MT) dynamics in TGF-beta1-induced actin cytoskeletal remodeling and EC barrier dysfunction. TGF-beta1 (0.1-50 ng/ml) induced dose-dependent decrease in transendothelial electrical resistance (TER) in bovine pulmonary ECs, which was linked to increased actin stress fiber formation, myosin light chain (MLC) phosphorylation, EC retraction, and gap formation. Inhibitor of TGF-beta1 receptor kinase RI (5 microM) abolished TGF-beta1-induced TER decline, whereas inhibitor of caspase-3 zVAD (10 microM) was without effect. TGF-beta1-induced EC barrier dysfunction was linked to partial dissolution of peripheral MT meshwork and decreased levels of stable (acetylated) MT pool, whereas MT stabilization by taxol (5 microM) attenuated TGF-beta1-induced barrier dysfunction and actin remodeling. TGF-beta1 induced sustained activation of small GTPase Rho and its effector Rho-kinase; phosphorylation of myosin binding subunit of myosin specific phosphatase; MLC phosphorylation; EC contraction; and gap formation, which was abolished by inhibition of Rho and Rho-kinase, and by MT stabilization with taxol. Finally, elevation of intracellular cAMP induced by forskolin (50 microM) attenuated TGF-beta1-induced barrier dysfunction, MLC phosphorylation, and protected the MT peripheral network. These results suggest a novel role for MT dynamics in the TGF-beta1-mediated Rho regulation, EC barrier dysfunction, and actin remodeling.

show abstract

Section: Discussionmentioning

confidence: 98%

Involvement of microtubules and Rho pathway in TGF‐β1‐induced lung vascular barrier dysfunction

Birukova¹,

Birukov²,

Adyshev³

et al. 2005

Journal Cellular Physiology

109

116

View full text Add to dashboard Cite

show abstract

“…Several kinases phosphorylate MAPs. These include extracellular signal regulated kinase (ERK), protein kinase A (PKA; on Thr220) [Alexa et al, ], protein kinase C (PKC; on Ser1703/Ser1711/Ser1728) [Ainsztein and Purich ] and c‐Jun N‐terminal kinase‐1 (JNK1; on Thr1619/The1622/Thr1623) in the proline rich domain (PRD) [Komulainen et al, ] (Table ). MAP2 is dephosphorylated by protein phosphatase‐1 (Sim ), –2A [Wera and Hemmings, ], –2B [Guerini, ] and –2C [Goldberg, ].…”

Section: Introductionmentioning

confidence: 99%

Microtubule and microtubule associated protein anomalies in psychiatric disease

2016

View full text Add to dashboard Cite

Anomalies in neuronal cell architecture, in particular dendritic complexity and synaptic density changes, are widely observed in the brains of subjects with schizophrenia or mood disorders. The concept that a disturbed microtubule cytoskeleton underlies these abnormalities and disrupts synaptic connectivity is supported by evidence from clinical studies and animal models. Prominent changes in tubulin expression levels are commonly found in disease specific regions such as the hippocampus and prefrontal cortex of psychiatric patients. Genetic linkage studies associate tubulinbinding proteins such as the dihydropyrimidinase family with an increased risk to develop schizophrenia and bipolar disorder. For many years, altered immunoreactivity of microtubule associated protein-2 has been a hallmark found in the brains of individuals with schizophrenia. In this review, we present a growing body of evidence that connects a dysfunctional microtubule cytoskeleton with neuropsychiatric illnesses. Findings from animal models are discussed together with clinical data with a particular focus on tubulin posttranslational modifications and on microtubule-binding proteins. V C 2016 Wiley Periodicals, Inc.Key Words: microtubule; depression; schizophrenia; MAP2; JNK Introduction I t is almost 50 years since tubulin was identified as the globular protein that makes up microtubules [Mohri, 1968]. Tubulin polymers, or microtubules, along with actin microfilaments and intermediate filaments, make up the cytoskeletal framework, which provides structure and dynamics to cells [Wells, 2005]. Neuronal cells are exceptional in their usage of microtubules to generate a highly polarized morphology consisting of long axons and dendritic arbors that form the receptive field for electrochemical input. Axonal microtubules are polarized and confer the rigidity that is necessary for long distance transport, whereas dendritic microtubules show mixed polarity and influence processes such as arborization and signaling to dendritic spines .In cells, a and b tubulin exist as heterodimers. They are structurally homologous, comprising two b-strands surrounded by a-helices. Each subunit is divided into three functional domains: the N-terminal domain that incorporates a nucleotide-binding region (i.e., GTP), an intermediate domain comprising the taxol-binding site, and a Cterminal domain which provides the binding surface for motor proteins [Nogales et al., 1998]. a/b heterodimers interact in a head-to-tail conformation giving rise to linear polymers with inherent polarity known as protofilaments [Black and Baas, 1989]. Typically, a microtubule consists of a cylindrical assembly of 13 protofilaments with a diameter of 25 nm, and highly variable length. Microtubules actively modify their structure through dynamic cycles of assembly and disassembly. The plus end where b-tubulin is exposed elongates more rapidly than the a-tubulin exposed, minus end [Horio et al., 2014]. The process of rapid growth and collapse of microtubules is known as dynamic instability a...

show abstract

“…MTs are hollow tubes of protofilaments, made up of virtual filaments of polymerized tubulin α/β heterodimers. Their stability and interactions with their environment depend on the presence and association of fully disordered accessory proteins, such as microtubule‐associated protein 2 (MAP2), tau protein, and stathmin [Alexa et al, ; Cassimeris, ; Dehmelt and Halpain, ]. The most diverse and versatile component of the cytoskeleton is microfilaments, which contain filamentous actin (F‐actin) regulated in diverse ways by largely disordered accessory/regulatory proteins (e.g., Tβ4 and Wiskott–Aldrich syndrome protein [WASP]).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Structural Disorder in Cytoskeletal Proteins

et al. 2013

View full text Add to dashboard Cite

Cytoskeleton, the internal scaffold of the cell, displays an exceptional combination of stability and dynamics. It is composed of three major filamentous networks, microfilaments (actin filaments), intermediate filaments (neurofilaments), and microtubules. Together, they ensure the physical and structural stability of the cell, whereby also mediating its large-scale structural rearrangements, motility, stress response, division, and internal transport. All three cytoskeletal systems are built upon the same basic design: they have a central repetitive scaffold assembled from folded building elements, surrounded and regulated by accessory regions/proteins that regulate its formation and mediate its countless interactions with its environment, serving to send regulatory signals to and from the cytoskeleton. Here, we elaborate on the idea that the opposing features of stability and dynamics are also manifest in the dichotomy of the structural status of its components, the core being highly structured and the accessory proteins/regions being highly disordered, and are responsible for most of the regulatory (post-translational) input promoting adaptive responses and providing dynamics necessary for each of the cytoskeletal systems. This pattern entails special consequences, in which the manifold functional advantages of structural disorder, most pronounced in regulatory and signaling functions, are all exploited by nature. (MTs), and it provides the internal scaffold (skeleton) of the cell. It can be considered as a very special organelle, which represents a unique combination of stability and dynamics, physical rigidity and flexibility, long-time persistence and rapid, cataclysmic rearrangements. By providing a special microenvironment, the cytoskeleton ensures the physical separation of cellular constituents, thus segregating and directing cellular activities. It bridges molecular (nano-m) and cellular (micro-m) distances and represent the tracks of transport of cellular constituents over large distances. It provides the locomotive force of cell migration, it drives clustering of membrane proteins, drives cell division and the formation of protrusions the cell uses for exploring its environment. Apparently it does it by a combination of a physically rigid but inherently unstable central scaffold and a flexible and rather variable outer layer of accessory proteins/regions. Due to its central importance in cell physiology, the cytoskeleton is involved in many diseases, ranging from cancer to neurodegeneration [Pajkos et al., 2012;Raychaudhuri et al., 2009;Uversky et al., 2008]. Our central theme here is that multifaceted and highly dynamic behavior is enabled by structural disorder in all three major cytoskeletal constituents, also reflecting their increasing complexity from NFs to the actin cytoskeleton (Supporting Information Table S1, Table I). Intermediate filaments (IFs) have three principal components, IF-L(ight), IF-M(edium), and IF-H(igh), all three of which form an extended coiled-coil structures, from which...

show abstract

The Phosphorylation State of Threonine-220, a Uniquely Phosphatase-Sensitive Protein Kinase A Site in Microtubule-Associated Protein MAP2c, Regulates Microtubule Binding and Stability

Cited by 21 publications

References 36 publications

Involvement of microtubules and Rho pathway in TGF‐β1‐induced lung vascular barrier dysfunction

Involvement of microtubules and Rho pathway in TGF‐β1‐induced lung vascular barrier dysfunction

Microtubule and microtubule associated protein anomalies in psychiatric disease

Intrinsic Structural Disorder in Cytoskeletal Proteins

Contact Info

Product

Resources

About