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PubMed1997

Is signal transduction modulated by an interaction between heterotrimeric G-proteins and tubulin?

Although it is generally accepted that tubulin plays an important role in G-protein-mediated signal transduction in a variety of systems, the mechanism of this phenomenon is not completely understood. G-protein-tubulin interaction at the cell membrane and the cytosol, and the influence of such an interaction on cellular signaling are discussed in this review article. Because the diameter of a microtubule is 25 nm and the plasma membrane is 9-11 nm thick, it is not possible for membrane-associated tubulin to assemble into a complete microtubule in the membrane environment. However, tubulin heterodimers may be able to function in the membrane environment as individual heterodimers or as polymers arranged into short protofilaments. At the cell membrane, membrane-associated tubulin may influence hormone-receptor interaction, receptor-G-protein coupling, and G-protein-effector coupling. Structural proteins, such as tubulin, can participate in cellular signaling by communicating through physical forces. By virtue of its interaction with the submembranous network of cytoskeletal proteins, tubulin, when perturbed in one locus, can transmit large changes in conformations to other points. Thus, GTP binding to membrane-associated tubulin might lead to a conformational change in either receptors or G proteins. This may, in turn, influence the binding of an agonist to its receptor. On the other hand, in the cell cytosol, subsequent to agonist-induced translocation of G-proteins from the membrane compartment to the cytosol, G-proteins may affect microtubule formation. In GH3 and AtT-20 cells (stably expressing TRH receptor), transiently transfected with Gq alpha cDNA, soluble tubulin levels decreased in Gq alpha-transfected GH3 and AtT-20 cells, by 33% and 52%, respectively. These results suggest that G-proteins may have a direct effect on the microtubule function in vivo. Because tubulin and G-protein families are ubiquitous and highly conserved, an interaction between these two protein families may occur in vivo, and this, in turn, can have an impact on signal transduction. However, the physiological significance of this interaction remains to be demonstrated.

Animals↗

PubMed2004

Sperm membrane protein (hSMP-1) and RanBPM complex in the microtubule-organizing centre.

hSMP-1 is a human sperm membrane protein expressed during development. It is a testis-specific component produced during male germ cell differentiation. Proteins that interact with hSMP-1 were identified by the application of the yeast two-hybrid system. One of the components, RanBPM, was found to be associated with hSMP-1 under both in vitro and in vivo conditions. In the human testis, RanBPM is produced in spermatogonia and primary spermatocytes, suggesting expression during the early stages of spermatogenesis; whereas in the rat testis, it is located in round and elongated spermatids, similar to hSMP-1, suggesting expression of both components during spermiogenesis. Images obtained by immunofluorescence and confocal scanning microscopy of CHO-K1 cells co-transfected with pEGFP-C1-hSMP-1 and pDsRed1-Nl-RanBPM revealed that RanBPM and hSMP-1 are distributed in discrete loci throughout the cytoplasm. When superimposed, the stained spots appeared as congruent yellow areas, indicative of co-localization and probable complex formation of these two components. This interaction between hSMP-1 and RanBPM may be involved in the process of male germ cell differentiation. In CHO-Kl cells transfected with pEGFP-Cl-hSMP-1, the exogenously expressed hSMP-1 was found to co-localize with alpha-tubulin. Depolymerization of microtubules can be induced in CHO-Kl cells by cold treatment. In cells transfected with the pEGFP-Cl vector, the dispersed tubulins promptly reassembled upon warming. However, in cells transfected with pEGFP-Cl-hSMP-1, reassembly of the dispersed tubulins was blocked even upon rewarming of the cells. These findings suggest that hSMP-1 interacts with tubulins and thereby may modulate microtubule assembly and/or activity.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Assay and functional analysis of the ARL3 effector RP2 involved in X-linked retinitis pigmentosa.

Mutations in RP2 cause X-linked retinitis pigmentosa and also macular and peripapillary atrophy. RP2 is a functional homologue of the tubulin folding cofactor, cofactor C, as it can replace the beta tubulin GTPase stimulating activity of cofactor C in an in vitro assay. An important difference between RP2 and cofactor C is their subcellular localization. RP2 is targeted to the cytoplasmic face of the plasma membrane by dual N-terminal acylation, and this post-translational modification is important for protein function. The activity of tubulin folding cofactors is modulated by certain ADP ribosylation factor-like (Arl) proteins. It has been shown that RP2 can interact directly with Arl3. Here we describe the methodologies that we have developed to analyze the interaction of RP2 with Arl3 and to investigate the effect of RP2 post-translational modifications on its subcellular and tissue localization.

ADP-Ribosylation Factors↗

PubMed1993

Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons.

Microtubules and their associated proteins play a prominent role in many physiological and morphological aspects of brain function. Abnormal deposition of the microtubule-associated proteins (MAPs), MAP2 and tau, is a prominent aspect of Alzheimer's disease. MAP2 and tau are heat-stable phosphoproteins subject to high rates of phosphorylation/dephosphorylation. The phosphorylation state of these proteins modulates their affinity for tubulin and thereby affects the structure of the neuronal cytoskeleton. The dinoflagellate toxin okadaic acid is a potent and specific inhibitor of protein phosphatases 1 and 2A. In cultured rat cortical neurons and a human neuroblastoma cell line (MSN), okadaic acid induces increased phosphorylation of MAP2 and tau concomitant with early changes in the neuronal cytoskeleton and ultimately leads to cell death. These results suggest that the diminished rate of MAP2 and tau dephosphorylation affects the stability of the neuronal cytoskeleton. The effect of okadaic acid was not restricted to neurons. Astrocytes stained with antibodies to glial fibrillary acidic protein (GFAP) showed increased GFAP staining and changes in astrocyte morphology from a flat shape to a stellate appearance with long processes.

Animals↗

PubMed1994

The role of cytoskeletal proteins in neutrophil emigration during pneumonia in rabbits.

The cytoskeletal proteins, actin and tubulin, are critical in modulating many aspects of the structural, mechanical, and biochemical properties of cells. This study determined if rearrangements of microtubules or filamentous actin were necessary for neutrophil margination within the pulmonary microvasculature or emigration into the alveolar spaces in response to Streptococcus pneumoniae. Microtubule assembly was inhibited using colchicine, and F-actin depolymerization was inhabited using phalloidin. Anesthetized rabbits received an intrabronchial instillation of S. pneumoniae either after intravenous pretreatment with colchicine (1 mg/kg every 2 h) or combined with TRITC-phalloidin (2 microM in instillate). Four hours later, the lungs were fixed and removed. The results show that the intravenous injection of colchicine caused a rapid decrease in circulating neutrophil counts, most likely caused by sequestration within the pulmonary microvasculature, that gradually recovered. In the pneumonic region, colchicine inhibited neutrophil emigration by 74 +/- 5%, but it did not prevent the stimulus-induced increase in margination. Phalloidin inhibited neutrophil emigration by 83 +/- 4%. These studies suggested that microtubule reassembly occurs during neutrophil transit through the normal pulmonary microvasculature and that it is required for migration but not sequestration during pneumonia. Rearrangement of actin filaments in lung cells but not neutrophils are required for neutrophil emigration induced by S. pneumoniae.

Actins↗

PubMed2006

Microtubule disassembly and inhibition of mitosis by a novel synthetic pharmacophore.

Microtubule drugs, which block cell cycle progression through mitosis, have seen widespread use in cancer chemotherapies. Although microtubules are subject to regulation by signal transduction mechanisms, their pharmacological modulation has so far relied on compounds that bind to the tubulin subunit. A new microtubule pharmacophore, diphenyleneiodonium, causing disassembly of the microtubule cytoskeleton is described here. Although this synthetic compound does not affect the assembly state of purified microtubules, it profoundly suppresses microtubule assembly in vivo, causes paclitaxel-stabilized microtubules to cluster around the centrosomes, and selectively disassembles dynamic microtubules. Similar to other microtubule drugs, this new pharmacophore blocks mitotic spindle assembly and mitotic cell division.

Animals↗

PubMed1990

Phorbol myristate acetate-induced down-modulation of CD4 is dependent on calmodulin and intracellular calcium.

PMA causes rapid down-modulation of CD4 molecules on murine immature thymocytes, human PBL, and CD4-positive human tumor cell lines, but not on murine peripheral lymphocytes. The mechanisms of phorbol ester-induced down modulation of CD4 molecules, however, have not been elucidated. To determine how PMA down-modulates CD4 expression by T lymphocytes, we studied the ability of inhibitors of protein kinase C, calmodulin, actin, and tubulin to block PMA-induced modulation of CD4 in several murine and human cell types. We also tested the ability of intracellular and extracellular calcium chelators to block CD4 internalization. There was marked variability in the degree of PMA-induced down-modulation of CD4 among various cell types. The effects of PMA on CD4 expression were greater for murine thymocytes, for human PBL, and for the human lymphoblastic leukemia cell line, MOLT-3, than for any of the other cell types studied. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, blocked phosphorylation but not internalization of CD4 molecules induced by PMA. Therefore, phosphorylation of CD4 molecules by protein kinase C is not required for the internalization of the molecules. Internalization was blocked by both inhibitors of calmodulin, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide, and trifluoperazine. PMA-induced internalization of CD4 was blocked by Quin-2 AM, which chelates intracellular calcium. EGTA, which chelates extracellular calcium, did not block internalization. Inhibitors of actin or tubulin did not block internalization. These results suggest that PMA-induced modulation of CD4 can occur in the absence of phosphorylation of the CD4 molecules and is calmodulin and intracellular calcium dependent.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1988

Regulation of microtubule protein levels during cellular morphogenesis in nerve growth factor-treated PC12 cells.

Nerve growth factor induces neurite process formation in pheochromacytoma (PC12) cells and causes the parallel increase in levels of the microtubule-associated proteins, tau and MAP1, as well as increases in tubulin levels. Mechanisms to insure balanced accumulation of microtubule proteins and make their levels highly responsive to nerve growth factor were investigated. The effects on tau, MAP1, and tubulin are due to changes in protein synthesis rates, which for tau and tubulin we could show are due in part to changes in the mRNA levels. Whereas tubulin shows feedback regulation to modulate synthesis up or down, tau protein synthesis is not affected in a straightforward way by microtubule polymerization and depolymerization. The degradation of tau, MAP1, and both tubulin polypeptides, however, are stimulated by microtubule depolymerization caused by colchicine, or nerve growth factor removal. Combined feedback on synthesis and stability make tubulin levels highly responsive to assembly states. In addition, the linkage of tau and MAP1 turnover with the state of microtubule polymerization amplifies any change in their rate of synthesis, since tau and MAP1 promote microtubule polymerization. This linkage lends itself to rapid changes in the state of the system in response to nerve growth factor.

Animals↗

PubMed1986

Characterization and structural aspects of the enhanced assembly of tubulin after removal of its carboxyl-terminal domain.

Limited subtilisin cleavage of tubulin results in formation of S-tubulin heterodimer and a 4-kDa carboxyl-terminal peptide fragment. This carboxyl-terminal domain constitutes an essential site for MAPs interaction and plays a role in modulating the interactions responsible for tubulin self-assembly into microtubules [Serrano et al. (1984) Proc. Natl Acad. Sci. USA 81, 5989; and Biochemistry 23, 4675]. In the present communication it is shown that addition of the 4-kDa peptide fragment from porcine tubulin to porcine S-tubulin in a molar ratio of about 2:1 does not affect the assembly of the latter. On the other hand, consistent with previous findings on the binding of the 4-kDa peptide by MAP-2, the peptide inhibited MAP-2-induced tubulin assembly (molar ratio of peptide to tubulin, about 2:1; peptide to MAP-2, about 30:1). Comparison of the amino acid composition of the 4-kDa peptide fragment and the C-terminal amino acid residues of S-tubulin with the amino acid sequence of tubulin indicated the subtilisin cleavage site on the tubulin molecule to be between residues Glu417 and Phe418 of the alpha-subunit sequence and between Glu407 and Phe408 of the beta-subunit sequence. The circular dichroism of the 4-kDa fragment in water as solvent is indicative of a molecule with an unordered structure, but when the solvent is changed to a water-trifluoroethanol mixture, the fragment becomes more highly structured. The critical concentration for S-tubulin assembly is not affected by MAPs nor by polylysine, but is decreased by either taxol of dimethylsulfoxide. S-tubulin, with its greater propensity for self-association, has a different conformation from tubulin as shown by a 50% decrease in alpha-helical content, a more hydrophobic environment of at least some of the tryptophan residues as judged from fluorimetry, and a greater compaction indicated by f/f0 = 1.3, as compared to 1.4 for tubulin. The latter point is supported by the observation that the value of the sedimentation coefficient, s20,w = 5.7 S, of the 92-kDa S-tubulin molecule is not significantly different from that of the 100-kDa tubulin, s20,w = 5.8S.

Amino Acids↗

PubMed2005

Soy isoflavones modulate the expression of BAD and neuron-specific beta III tubulin in male rat brain.

Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. There is evidence that soy isoflavones influence neuronal apoptosis or proliferation in vitro and in vivo. However, little research has been done to investigate the effects of soy isoflavones on markers of neuronal apoptosis and survival in vivo. We examined brain BAD (a proapoptotic member of Bcl-2 protein family) and neuron-specific beta III tubulin (an early marker of neuronal differentiation/survival) levels in male rats fed either a standard chow rich of soy isoflavones (Phyto-600) or one free of soy isoflavones (Phyto-free) life-long (from conception until time tissue collected). Among five brain regions, the expression of BAD was highest in medial basal hypothalamus (MBH); the next highest in hippocampus; moderate in amygdala and frontal cortex; and lowest in cerebellum in Phyto-free fed animals. In animals on Phyto-600 diet, the levels of BAD were significantly decreased in frontal cortex and MBH; but significantly increased in the amygdala. The expression of beta III tubulin was highest in frontal cortex; moderate in amygdala, hippocampus and MBH; and lowest in cerebellum in the Phyto-free group. In rats fed with the Phyto-600 diet, levels of beta III tubulin were significantly increased in amygdala, frontal cortex, hippocampus and MBH compared to Phyto-free values. In summary, these findings provide evidence for the neuroprotective potential of soy isoflavones in the amygdala, frontal cortex, hippocampus and MBH. This implies that consumption of soy isoflavones may be beneficial on learning and memory, anxiety-related behaviors, and recovery from trauma.

Animals↗

PubMed1992

Regulation of the microtubule nucleating activity of centrosomes in Xenopus egg extracts: role of cyclin A-associated protein kinase.

Isolated centrosomes nucleate microtubules when incubated in pure tubulin solutions well below the critical concentration for spontaneous polymer assembly (approximately 15 microM instead of 60 microM). Treatment with urea (2-3 M) does not severely damage the centriole cylinders but inactivates their ability to nucleate microtubules even at high tubulin concentrations. Here we show that centrosomes inactivated by urea are functionally complemented in frog egg extracts. Centrosomes can then be reisolated on sucrose gradients and assayed in different concentrations of pure tubulin to quantify their nucleating activity. We show that the material that complements centrosomes is stored in a soluble form in the egg. Each frog egg contains enough material to complement greater than 6,000 urea-inactivated centrosomes. The material is heat inactivated above 56 degrees C. One can use this in vitro system to study how the microtubule nucleating activity of centrosomes is regulated. Native centrosomes require approximately 15 microM tubulin to begin nucleating microtubules, whereas centrosomes complemented in interphase extracts begin nucleating microtubules around 7-8 microM tubulin. Therefore, the critical tubulin concentrations for polymer assembly off native centrosomes is higher than that observed for the centrosomes first denatured and then complemented in egg extracts. In vivo, the microtubule nucleating activity of centrosomes seems to be regulated by phosphorylation at the onset of mitosis (Centonze, V. E., and G. G. Borisy. 1990. J. Cell Sci. 95:405-411). Since cyclins are major regulators of mitosis, we tested the effect of adding bacterially produced cyclins to interphase egg extracts. Both cyclin A and B activate an H1 kinase in the extracts. Cyclin A-associated kinase causes an increase in the microtubule nucleating activity of centrosomes complemented in the extract but cyclin B does not. The critical tubulin concentration for polymer assembly off centrosomes complemented in cyclin A-treated extracts is similar to that observed for centrosomes complemented in interphase extracts. However, centrosomes complemented in cyclin A treated extracts nucleate much more microtubules at high tubulin concentration. We define this as the "capacity" of centrosomes to nucleate microtubules. It seems that the microtubule nucleating activity of centrosomes can be defined by two distinct parameters: (a) the critical tubulin concentration at which they begin to nucleate microtubules and (b) their capacity to nucleate microtubules at high tubulin concentrations, the latter being modulated by phosphorylation.

Adenosine Triphosphate↗

PubMed1988

Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin.

Tubulin synthesis in animal cells is controlled by an autoregulatory mechanism that modulates the stability of polysome-bound tubulin messenger RNAs. The beta-tubulin RNAs are selectively targeted as substrates for destabilization not through the recognition of specific RNA sequences, but rather through co-translational recognition of the amino-terminal beta-tubulin tetrapeptide after its emergence from the ribosome. This motif is likely to be used in other systems where RNA degradation is coupled to ribosome attachment and translation.

Amino Acid Sequence↗

PubMed1988

Agonist-induced changes of platelet tubulin phosphorylation.

Changes in the phosphorylation of platelet tubulin were analyzed as a function of platelet activation. Non-activated platelets incubated with [32P]-phosphate showed multiple peaks of radioactivity when solubilized platelet proteins were analyzed by SDS-polyacrylamide gradient gel electrophoresis. Both tubulin monomers were found to be phosphorylated. Agonistic stimulation (thrombin or 1,2-diacylglycerol) resulted in a lowering of the phosphate incorporation into alpha- and beta-tubulin. Such changes we believe are important in the modulation of the reversible polymerization-depolymerization of platelet tubulin that occurs in the course of the agonistic stimulation of platelets.

Autoradiography↗

PubMed2004

Integrity of actin fibers and microtubules influences metastatic tumor cell adhesion.

Tumor cell adhesion within host organ microvasculature, its stabilization and invasion into host organ parenchyma appear to be important steps during formation of distant metastasis. These interactions of circulating tumor cells with the host organs occur in the presence of fluid shear forces and soluble and cellular environmental conditions of the blood that can modulate their cellular responses and possibly their metastatic efficiency. Cytoskeletal components, such as actin filaments and microtubules, can regulate biophysical characteristics and cellular signaling of the circulating cells. Therefore, we investigated the role of these cytoskeletal structures for early steps during metastasis formation in vivo and in vitro. Using an intravital observation technique, tumor cell adhesion of colon carcinoma cells within the hepatic microcirculation of rats and their invasion into liver parenchyma was observed. Disruption of actin filaments increased cell adhesion, whereas tubulin disruption inhibited adhesive interactions in vivo. The impairment of the cytoskeleton modulated adhesion-mediated cell signaling via focal adhesion kinase (FAK) and paxillin under flow conditions in vitro. In the presence of fluid flow, focal adhesions were enlarged and hyperphosphorylated, whereas stress fibers were reduced compared to static cell adhesion. Disruption of microtubules, however, partially inhibited these effects. Combining the in vivo and in vitro results, our study suggested that changes in cell rigidity and avidity of cell adhesion molecules after disruption of cytoskeletal components appear to be more important for initial adhesive interactions in vivo than their interference with adhesion-mediated cellular signal transduction.

Actin Cytoskeleton↗

PubMed1990

Effect of polyanions and polycations on detyrosination of tubulin and microtubules at steady state.

Microtubule protein preparations purified from rat brain were used to study the effect of polycations and polyanions on the release of the COOH-terminal tyrosine of the alpha-chain of tubulin catalyzed by tubulin carboxypeptidase. (1) Most of the polycations and polyanions tested, independently of the ionogenic group, inhibited the reaction in a concentration-dependent fashion. Under steady-state conditions, detyrosination of the microtubule pool was inhibited to the same degree as occurred with the non-assembled tubulin pool, except in the case of chondroitin sulphate. This compound inhibited detyrosination of the non-assembled tubulin pool, but not that of microtubules. (2) Heparin, the most potent inhibitor tested, produced the dissociation of the carboxypeptidase from microtubules. Many, but not all, of the other microtubule-associated polypeptides were also dissociated by heparin. (3) Polylysine counteracted the inhibitory and dissociating effects of heparin. (4) Heparin protected tubulin carboxypeptidase against inactivation. Our results and previous reports describing, in nervous tissue, the presence of proteoglycans, RNA and basic proteins that inhibit detyrosination, suggest that tubulin carboxypeptidase might be physiologically modulated by electrically charged macromolecules.

Animals↗

PubMed1996

[Microtubules: functional polymorphisms of tubulin and associated proteins (structural and motor MAP's)].

In neuronal cells, microtubules are built from a very large number of alpha- and beta-tubulin variants. This diversity is due to the expression of a multigene family and to a combination of several original posttranslational modifications. Similarly, structural and motor microtubule-associated proteins, which regulate the assembly of microtubules, the modeling of their network and the mediation of their functions, are also very heterogeneous. As a consequence, mixing of these two protein polymorphisms leads to the formation of functionally-distinct microtubules. We have shown that polyglutamylation, the major posttranslational modification of neuronal tubulin, was used as a progressive regulator in the binding of structural and motor microtubule-associated proteins, in modulating gradually the conformation of the tubulin carboxy-terminal domain, playing thus a crucial role in microtubule dynamics.

Animals↗

PubMed2002

P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer cells to tubulin-binding anticancer drugs.

Alterations in metabolism of ceramide (Cer) to the noncytotoxic metabolite glucosylceramide have been implicated in the multidrug resistance (MDR) phenomenon. This observation has been made with tumor cells that also overexpress P-glycoprotein (Pgp), raising the possibility that Pgp plays a role in regulating Cer metabolism. We investigated the effect of the glucosylceramide synthase inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) on the chemosensitivity of two wild-type and multidrug-resistant human breast tumor cell lines. Subtoxic concentrations of PDMP sensitized drug-selected MCF7/AdrR and Pgp-overexpressing MDA435/LCC6MDR1 (MDR1 gene-transfected) cell lines to Taxol and vincristine but did not alter the chemosensitivity of the wild-type cells. Evaluation of Taxol uptake indicated that the effect of PDMP was not due to membrane permeability alterations because anticancer drug accumulation was unaffected by PDMP. Whereas both multidrug-resistant cell lines overexpress Pgp, only the MCF7/AdrR cell line overexpresses the glucosylceramide synthase enzyme. This difference enabled us to distinguish between sensitization effects associated with Cer metabolism versus Pgp-mediated transport. Interestingly, when Pgp function was blocked, the PDMP effect was reduced 3-fold in MCF7/AdrR cells and was no longer observed in the MDA435/LCC6MDR1 cells. These observations imply that Cer metabolism and apoptosis effects are regulated not only by enzymes that convert Cer to nontoxic metabolites but also by Pgp-mediated transport. Given the intracellular distribution patterns of Pgp, we propose that this effect is related to glucosylceramide translocation across the Golgi bilayer. We have applied this model to the situation of Cer metabolism-based chemosensitization and demonstrate that MDR modulation strategies aimed primarily at altering drug transport mechanisms can influence other MDR mechanisms such as glycosphingolipid metabolism. This work highlights the relationship between drug transport and Cer metabolism in the context of chemosensitization and cautions against making oversimplified assumptions that these mechanisms act independently.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Farnesyl pyrophosphate promotes and is essential for the binding of RACK1 with beta-tubulin.

Receptors for activated C kinase (RACKs) are a group of protein kinase C (PKC) binding proteins that have been shown to be crucial in the translocation and subsequent functioning of PKC on activation. RACK1 isolated from BALB/3T3 cells transformed with S-ras(Q61K) exhibits receptor activity for PKCgamma as competent as that of RACK1 from BALB/3T3 cells without transformation. However, the ability of RACK1 from transformed cells to bind with beta-tubulin peptide specific for Taxol (PEPtaxol) is defective. Interestingly, when farnesyl pyrophosphate was added at the submicrogram level, the association between RACK1 and PEPtaxol was enhanced significantly in a dosage-dependent manner. A parallel finding for the enhanced effect of farnesyl pyrophosphate on tubulin binding was established with mice RACK1 expressed in vitro. On the other hand, geranylgeranyl pyrophosphate, and retinoic acid failed to modulate the binding between RACK1 and tubulin. The dissociation of RACK1 and tubulin was not effective at damaging the binding between RACK1 and membrane receptor integrin beta1 in transformed cells. These findings indicate that depletion of farnesyl pyrophosphate provides a mechanism to seal PKC signaling on the membrane with immobile RACK1 and to divert cells to aberrant growth, such as transformation.

3T3 Cells↗