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BBA - Molecular Cell Research (v.1803, #9)

Editorial Board (pp. i).

The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogenesis by Alberto M. Martelli; Camilla Evangelisti; Francesca Chiarini; Cecilia Grimaldi; Alessandra Cappellini; Andrea Ognibene; James A. McCubrey (pp. 991-1002).

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway mediates diverse and important physiological cell functions which include proliferation, differentiation, survival, motility, autophagy, and metabolism. However, dysregulated PI3K/Akt/mTOR signaling has been documented in a wide range of neoplasias, including malignant hematological disorders. It is now emerging that this signaling network plays a key role during normal hematopoiesis, a tightly regulated process resulting in the formation of all blood lineages. Blood cell development encompasses a complex series of events which are mainly regulated by actions of cytokines, a family of extracellular ligands which stimulate many biological responses in a wide array of cell types. Hematopoiesis is strictly dependent on the correct function of the bone marrow microenvironment (BMM), as BMM cells secrete most of the cytokines. Several of these cytokines activate the PI3K/Akt/mTOR signaling network and regulate proliferation, survival, and differentiation events during hematopoiesis. Here, we review the evidence that links the signals emanating from the PI3K/Akt/mTOR cascade with the functions of hematopoietic stem cells and the process of myelopoiesis, including lineage commitment. We then highlight the emerging role played by aberrant PI3K/Akt/mTOR signaling during leukemogenesis.

Keywords: PI3K/Akt/mTOR; Hematopoietic stem cell; Signal transduction; Proliferation; Differentiation; Leukemia

DUSP26 negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs by Kate I. Patterson; Tilman Brummer; Roger J. Daly; Philippa M. O'Brien (pp. 1003-1012).

Dual specificity phosphatases are characterised by their ability to dephosphorylate both phosphotyrosine and phosphoserine/threonine residues within the one substrate. The aim of this study was to characterise the phosphatase activity of the atypical dual specificity phosphatase, DUSP26 on MAP kinases, and to determine its expression, regulation and function in cancer cells. Overexpression and knockdown of DUSP26 in epithelial cells and in vitro phosphatase assays were used to demonstrate that, contrary to several published reports, DUSP26 does not act as a dual specificity phosphatase on ERK, JNK or p38 MAPKs. However, overexpression of DUSP26 in MCF10A epithelial cells suppressed colony formation and acinar growth in 3D culture, effects dependent on its phosphatase activity, while knockdown of DUSP26 in HOSE17.1 cells enhanced colony formation and cellular proliferation. DUSP26 mRNA expression was reduced in neuroblastoma, brain and ovarian cancer cell lines. Consistent with epigenetic silencing of DUSP26, expression was enhanced by treatment of cells with 5-aza-2-deoxycitidine and trichostatin A, and a CpG island upstream of the DUSP26 transcriptional start site was variably methylated in cancer cell lines. Together, these results help to clarify confusion in the literature relating to DUSP26 substrate specificity and support recent reports that substrates other than MAPKs are the primary substrates of this phosphatase. In addition, they indicate that DUSP26 may function as a tumour suppressor in particular cancers.

Keywords: Abbreviations; TSA; Trichostatin A; 5'AZA; 5-aza-2-deoxycitidine; DUSP; dual specificity phosphatase; PTP; protein tyrosine phosphatase; MAPK; mitogen-activated protein kinase; pNPP; p; -nitrophenyl phosphate; GFP; green fluorescent proteinDual specificity phosphatase; Phosphatase; MAP kinase

cAMP-mediated regulation of HNF-4α depends on the level of coactivator PGC-1α by Simon Nitter Dankel; Tuyen Hoang; Flageng Marianne Hauglid Flågeng; Jørn Vegard Sagen; Gunnar Mellgren (pp. 1013-1019).

Hepatocyte nuclear factor-4 alpha (HNF-4α) is a member of the nuclear receptor superfamily with important roles in hepatic metabolism. Fasting induces the cAMP/protein kinase A (PKA)-signaling pathway. The mechanisms whereby cAMP regulates HNF-4α transcriptional activity are incompletely understood. We have therefore investigated the role of cAMP/PKA in regulation of HNF-4α in COS-1 cells and the hepatoma HepG2 cell line. cAMP/PKA inhibited the transcriptional activity of HNF-4α in COS-1 cells, whereas a stimulatory effect was observed in HepG2 cells. The cAMP-induced inhibition of HNF-4α in COS-1 cells was counteracted by overexpression of the nuclear receptor coactivator PGC-1α, and cAMP/PKA-dependent induction of the PGC1A gene in HepG2 cells seems to explain the cell specific differences. This was further supported by knock-down of PGC-1α in HepG2 cells, which abolished the stimulatory effect of PKA on HNF-4α transcriptional activity. Similar to the cAMP/PKA-mediated regulation of HNF-4α, overexpression of the cAMP-response element binding protein (CREB) inhibited the transcriptional activity of HNF-4α in COS-1 cells, regardless of cAMP/PKA activation and CREB phosphorylation. Moreover, activation of CREB by cAMP/PKA further stimulated HNF-4α transactivation in HepG2 cells. cAMP induced the expression of the HNF-4α target genes PCK1 and G6Pase in these cells. In conclusion, our results suggest that the level of PGC-1α determines whether the cAMP/PKA-pathway overall stimulates or inhibits HNF-4α transcriptional activation.

Keywords: Abbreviations; 8-CPT; 8-parachlorophenylthio; cAMP; cyclic adenosine monophosphate; CREB; cAMP-response element binding protein; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; G6Pase; glucose-6-phosphatase; HNF-4α; hepatocyte nuclear factor 4α; NR; nuclear receptor; PBGD; porphobilinogen deaminase; PCK1; phosphoenolpyruvate carboxykinase; PGC-1α; peroxisome proliferator-activated receptor gamma coactivator-1alpha; PKA; protein kinase A; TBP; tata-box binding proteinNuclear receptor; Coactivator; PKA; CREB; PGC-1α; HNF-4α

Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms by Mayumi Nakashima; Hiroshi Hamajima; Jinghe Xia; Shinji Iwane; Yasunori Kwaguchi; Yuichiro Eguchi; Toshihiko Mizuta; Kazuma Fujimoto; Iwata Ozaki; Sachiko Matsuhashi (pp. 1020-1027).

Transforming growth factor-β1 (TGF-β1) induces apoptosis in normal hepatocytes and hepatoma cells. PDCD4 is involved in TGF-β1-induced apoptosis via the Smad pathway. The tumor promoter 12-O-tetradecanoylphorbor-13-acetate (TPA), a protein kinase C stimulator, inhibits TGF-β1-induced apoptosis. However, the mechanisms of TPA action on PDCD4 expression remain to be elucidated. Therefore. the regulatory mechanism of PDCD4 expression by PKC was investigated. The treatment of the human hepatoma cell line, Huh7 with TPA suppressed PDCD4 protein expression and TGF-β1 failed to increase the PDCD4 protein expression. PKC inhibitors Ro-31-8425 or bisindolylmaleimide-1-hydrocholoride (pan-PKC inhibitors) and rottlerin (PKCδ inhibitor), but not Go6976 (PKCα inhibitor), enhanced the induction of PDCD4 protein by TGF-β1. Furthermore, siRNA-mediated knockdown of PKCδ and ε, but not PKCα, augmented the TGF-β1-stimulated PDCD4 protein expression. However, TPA or pan-PKC inhibitor did not alter the PDCD4 mRNA expression either under basal- and TGF-β1-treated conditions. The down-regulation of PDCD4 by TPA was restored by treatment with the proteasome inhibitor MG132. These data suggest that two isoforms of PKCs are involved in the regulation of the PDCD4 protein expression related to the proteasomal degradation pathway.

Keywords: PDCD4; Novel PKC; TPA; Hepatocellular carcinoma

Identification of an atypical peptidyl-prolyl cis/trans isomerase from trypanosomatids by Esteban D. Erben; Ezequiel Valguarnera; Sheila Nardelli; Janete Chung; Sebastian Daum; Mariana Potenza; Sergio Schenkman; Tellez-Inon María T. Téllez-Iñón (pp. 1028-1037).

The parvulin family of peptidyl-prolyl cis/trans isomerases (PPIases) catalyzes the cis/trans isomerization of the peptide bonds preceding Pro residues. Eukaryotic parvulin-type PPIases have been shown to be involved in cell proliferation and cell cycle progression. Here we present the biochemical and molecular characterization of a novel multi-domain parvulin-type PPIase from the human pathogenic Trypanosoma cruzi, annotated as TcPar45. Like most other parvulins, Par45 has an N-terminal extension, but, in contrast to human Pin1, it contains a forkhead-associated domain (FHA) instead of a WW domain at the N-terminal end. Par45 shows a strong preference for a substrate with the basic Arg residue preceding Pro (Suc-Ala-Arg-Pro-Phe-NH-Np: k_cat/ K_M=97.1 /M/s), like that found for human Par14. In contrast to human Pin1, but similarly to Par14, Par45 does not accelerate the cis/trans interconversion of acidic substrates containing Glu-Pro bonds. It is preferentially located in the parasite nucleus. Single RNA interference (RNAi)-mediated knock-down showed that there was a growth inhibition in procyclic Trypanosoma brucei cells. These results identify Par45 as a phosphorylation-independent parvulin required for normal cell proliferation in a unicellular eukaryotic cell.

Keywords: Abbreviations; FHA; forkhead-associated domain; NH-Np; 4-nitroanilide; PPIase; peptidyl-prolyl; cis/trans; isomerase; Par45; ^PPIase; residues 241–421 of; Tc; Par45Peptidyl-prolyl; cis/trans; isomerase; Parvulin; Pin1-type PPIase; Par45

The moonlighting function of pyruvate carboxylase resides in the non-catalytic end of the TIM barrel by Daphne H.E.W. Huberts; Hanka Venselaar; Gert Vriend; Marten Veenhuis; Ida J. van der Klei (pp. 1038-1042).

Pyruvate carboxylase is a highly conserved enzyme that functions in replenishing the tricarboxylic acid cycle with oxaloacetate. In the yeast Hansenula polymorpha, the pyruvate carboxylase protein is also required for import and assembly of the peroxisomal enzyme alcohol oxidase. This additional role, which is unrelated to the enzyme activity, represents an example of a special form of multifunctionality called moonlighting. We have performed a detailed site-directed mutagenesis approach to elucidate which region(s) of H. polymorpha pyruvate carboxylase are involved in its second function. This resulted in the identification of three amino acids that are essential for the moonlighting function. Mutating these residues in a single mutant protein fully inactivated the moonlighting function, but not the enzyme activity of pyruvate carboxylase because the strain was prototrophic. A 3D homology model revealed that all three residues are positioned at the side of a TIM barrel where the N-terminal ends of the β-strands are located. This is a novel observation as the TIM barrel proteins invariably are enzymes and have their catalytic side at the C-terminal end of the β-sheets. Our finding implies that a TIM barrel fold can also fulfill a non-enzymatic function and that this function can reside at the N-terminal end of the barrel.

Keywords: Abbreviations; Pyc1; pyruvate carboxylase; AO; alcohol oxidase; BC domain; biotin carboxylase domain; TC domain; transcarboxylase domain; BCC domain; biotin carboxylase carrier domain; I; identityPyruvate carboxylase; Moonlighting protein; TIM barrel; Alcohol oxidase; Peroxisome

Morgana/CHP-1 is a novel chaperone able to protect cells from stress by Wojciech Michowski; Roberta Ferretti; Marta B. Wisniewska; Mateusz Ambrozkiewicz; Malgorzata Beresewicz; Federica Fusella; Anna Skibinska-Kijek; Barbara Zablocka; Mara Brancaccio; Guido Tarone; Jacek Kuznicki (pp. 1043-1049).

Morgana/CHP-1 (CHORD containing protein-1) has been recently shown to be necessary for proper cell divisions. However, the presence of the protein in postmitotic tissues such as brain and striated muscle suggests that morgana/CHP-1 has additional cellular functions. Here we show that morgana/CHP-1 behaves like an HSP90 co-chaperone and possesses an independent molecular chaperone activity towards denatured proteins. The expression time profile of morgana/Chp-1 in NIH3T3 cells in response to heat stress is similar to that of Hsp70, a classical effector of Heat Shock Factor-1 mediated stress response. Moreover, overexpression of morgana/CHP-1 in NIH3T3 cells leads to the increased stress resistance of the cells. Interestingly, morgana/Chp-1 upregulation in response to transient global brain ischemia lasts longer in ischemia-resistant regions of the gerbil hippocampus than in vulnerable ones, suggesting the involvement of morgana/CHP-1 in natural protective mechanisms in vivo.

Keywords: Abbreviations; HSF-1; Heat Shock Factor-1; CHP-1; CHORD containing protein-1; CHORD; Cysteine and Histidine Rich Domain; HSP; Heat Shock Protein; CS; CHORD containing protein and SGT1 domainMorgana/CHP-1; CHORD; Co-chaperone; Heat shock protein; HSP90; stress

Aminoacyl-tRNA synthetases are multivalent suppressors of defects due to human equivalent mutations in yeast mt tRNA genes by Arianna Montanari; Cristina De Luca; Laura Frontali; Silvia Francisci (pp. 1050-1057).

The use of the yeast model for the study of the molecular and cellular effects of the pathogenic base substitutions in human mitochondrial tRNA genes has recently been validated by the finding that the suppressing factors identified in yeast (the mitochondrial protein elongation factor EF-Tu and the cognate aminoacyl-tRNA synthetase) have suppressing activities also in human cells. In this paper we report a detailed analysis of the cross-suppressing activities of valyl- and leucyl-tRNA synthetases on different tRNA mutants. Glycerol growth, respiration, Northern analysis consistently show that similar suppressing effects can be obtained by these two yeast synthetases and by the orthologous human enzymes. As a whole the present data indicate that the suppression by mt aa-RS is probably not related to the enzyme activities per se, and may be due to a stabilizing chaperon-like effect of the synthetase molecules on the tRNA structure altered by the mutations.

Keywords: Abbreviations; mt; mitochondrial; bp; base-pair; MELAS; mitochondrial encephalomyophathy, lactic acidosis, and stroke-like episodes; aa-RS; aminoacyl-tRNA synthetase; rho; ⁺; (mt DNA wild-type); rho° (mt DNA absent), rho; ⁻; (large mt DNA deletion)Mitochondria; Mitochondrial diseases; Aminoacyl-tRNA synthetase

On the organization of the nucleosomes associated with telomeric sequences by Francisco M. Gámez-Arjona; Carmen López-López; María I. Vaquero-Sedas; Miguel A. Vega-Palas (pp. 1058-1061).

The functions of telomeres and, probably, of interstitial telomeric sequences (ITSs) are influenced by their chromatin structure and organization. Telomeres in higher eukaryotes fold into nucleosomes that are about 20–40 bp shorter than the nucleosomes associated with bulk chromatin. Although the functional relevance of this short nucleosomal organization remains unknown, it is believed that short nucleosomes should contribute to telomere function. Whereas telomeric nucleosomes have been widely studied in different organisms, very little is known about the nucleosomal organization of ITSs. Chinese hamster ITSs have been found to associate with short nucleosomes. However, we have found that Arabidopsis thaliana ITSs fold into nucleosomes that have a repeat length similar to bulk chromatin. We discuss how the primary sequence of telomeres and ITSs could influence their nucleosomal organization.

Keywords: Telomere; Nucleosome positioning; Arabidopsis

Characterization of nuclear factors modulating the apolipoprotein D promoter during growth arrest: Implication of PARP-1, APEX-1 and ERK1/2 catalytic activities by Louis-Charles Levros Jr.; Sonia Do Carmo; Elsy Edouard; Philippe Legault; Cyndia Charfi; Eric Rassart (pp. 1062-1071).

Human Apolipoprotein D (apoD) is upregulated under several stress conditions and pathological situations such as neurodegenerative diseases and cancers. We previously showed that apoD mRNA expression is induced in growth-arrested cells and demonstrated the specific binding of nuclear proteins to the region −514 to −475 of the promoter. Such region contains a pair of Serum Responsive Elements (SRE), an Ets-Binding Site (EBS) and a Glucocorticoid Responsive Element (GRE). In this study, we show that Parp-1, HnRNP-U, CBF-A, BUB-3, Kif4, APEX-1 and Ifi204 bind these regulatory elements of the apoD promoter. Specific binding of HnRNP-U and Parp-1 was confirmed by Electrophoretic Mobility Shift Assay (EMSA). In a biotin pull-down assay, Kif4 and BUB-3 bind preferentially the SRE1 and the EBS-GRE sites, respectively, while APEX-1 seems recruited indirectly to these elements. We found that the mRNA expression of some of these binding factors is upregulated in growth-arrested cells and that these proteins also transactivate the apoD promoter. In agreement with these results, mutants of APEX-1 and of Parp-1 defective for their DNA-binding and catalytic activities could not transactivate the promoter. The knockdown of Parp-1 and HnRNP-U and the use of specific inhibitors of MEK1/2 and of Parp-1 also inhibited the induction of apoD gene expression. Moreover, ERK1/2 was found activated in a biphasic manner post serum-starvation and the inhibition of Parp-1 causes a sustained activation of ERK2 but not ERK1 for up to 2h. Altogether, these findings demonstrate the importance of Parp-1, APEX-1 and ERK1/2 catalytic activities in the growth arrest-induced apoD gene expression.

Keywords: Abbreviations; apoD; apolipoprotein D; SRE; Serum responsive element; EBS; Ets-Binding site; GRE; Glucocorticoid responsive element; EMSA; Electrophoretic Mobility Shift Assay; HnRNP; Heterogeneous nuclear ribonucleoprotein; CBF-A; CArG-box Binding Factor A (CBF-A); Parp-1; Poly(ADP-ribose) polymerase-1; Ifi204; Interferon-inducible protein 204; APEX-1; Apurinic/Apyrimidinic Endonuclease-1; Kif4; Kinesin family member 4; BUB-3; Budding Uninhibited by Benzimidazole 3; KifC1; Kinesin family member C1; Rbp1; Ribosome-binding protein 1Apolipoprotein D (apoD); Cellular stress; Growth arrest; DNA binding proteins; PARP-1; APEX-1; HnRNP-U; IFI204; Kif4; BUB-3; ERK1/2

Different oxidants and PKC isozymes mediate the opposite effect of inhibition of Q_i and Q_o site of mitochondrial complex III on calcium currents in rat cortical neurons by Pei-Ying Wu; Bin Lai; Yi Dong; Ze-Min Wang; Zi-Cheng Li; Ping Zheng (pp. 1072-1082).

The inhibition of the complex III of the mitochondrial respiratory chain under hypoxia-ischemia has been observed. However, the downstream events of this inhibition remain to be studied. In this paper, we used the Q_i site inhibitor antimycin A and the Q_o site inhibitor myxothiazol to inhibit the Q_i site and the Q_o site of the complex III and studied the effect and mechanism of the inhibition of these sites on voltage-gated Ca²⁺ currents (I_Ca) in rat prefrontal neurons with whole cell patch-clamp method in slices. The results showed that antimycin A inhibited I_Ca, but myxothiazol increased it. Further mechanism study showed that antimycin A inhibited I_Ca via the H₂O₂-hydroxyl radicals/cPKC (mainly PKCβI) pathway, whereas myxothiazol increased I_Ca via the superoxide anion/nPKC (mainly the PKCδ) pathway.

Keywords: Cortical neurons; Mitochondrial complex III; Whole-cell patch-clamp; Calcium currents; Reactive oxygen species; Protein kinase C

Lipid rafts modulate the activation but not the maintenance of store-operated Ca²⁺ entry by Carmen Galan; Geoffrey E. Woodard; Natalia Dionisio; Gines M. Salido; Juan A. Rosado (pp. 1083-1093).

Different studies have reported that proteins involved in Ca²⁺ entry are localized in discrete plasma membrane domains known as lipid rafts, which have been suggested to support store-operated Ca²⁺ entry by facilitating STIM1 clustering in endoplasmic reticulum–plasma membrane junctions as well as the interaction of STIM1 with TRPC1. Here we report that treatment of HEK293 cells with thapsigargin (TG) results in the activation of Ca²⁺ entry with two components, an early, La³⁺-sensitive, component and a late component that shows both La³⁺-sensitive and -insensitive constituents. Preincubation with methyl-β-cyclodextrin (MβCD) prevented TG-induced activation of Ca²⁺ entry but, in contrast, enhanced this process after its activation. Addition of MβCD after store depletion did not modify the La³⁺-sensitive store-operated divalent cation entry but increased La³⁺-insensitive non-capacitative Ca²⁺ entry. Cell stimulation with TG results in a transient increase in Orai1 co-immunoprecipitation with STIM1, TRPC1 and TRPC6. TG-induced association of these proteins was significantly attenuated by preincubation for 30min with MβCD, without altering surface expression of Orai1 or TRPCs. In contrast, the association of Orai1 with STIM1 or TRPC1 was unaffected when MβCD was added after store depletion with TG. Addition of MβCD to TG-treated cells promoted dissociation between Orai1 and TRPC6, as well as non-capacitative Ca²⁺ entry. TRPC6 expression silencing indicates that MβCD-enhanced non-capacitative Ca²⁺ entry was mediated by TRPC6. In conclusion, lipid raft domains are necessary for the activation but not the maintenance of SOCE probably due to the support of the formation of Ca²⁺ signalling complexes involving Orai1, TRPCs and STIM1.

Keywords: Abbreviations; [Ca; ²⁺; ]; _c; intracellular free calcium concentration; BSA; bovine serum albumin; CLM; cholesterol-loaded methyl-β-cyclodextrin; ER; endoplasmic reticulum; HEK293 cells; Human embryonic kidney 293 cells; HBS; HEPES-buffered saline; MβCD; methyl-β-cyclodextrin; PBS; phosphate-buffered saline; PM; plasma membrane; SOCE; store-operated calcium entry; STIM1; stromal interaction molecule 1; TBST; tris-buffered saline with 0.1% Tween 20; TG; thapsigargin; TRP; transient receptor potentialOrai1; TRPC1; TRPC6; STIM1; Lipid rafts; Lanthanum

Accumulation of polyubiquitylated proteins in response to Ala-Ala-Phe-chloromethylketone is independent of the inhibition of tripeptidyl peptidase II by Eugenia M. Villasevil; Sara Guil; Lopez-Ferreras Lorena López-Ferreras; Sanchez Carlos Sánchez; Margarita Del Val; Anton Luis C. Antón (pp. 1094-1105).

In the present study we have addressed the issue of proteasome independent cytosolic protein degradation. Tripeptidyl peptidase II (TPPII) has been suggested to compensate for a reduced proteasome activity, partly based on evidence using the inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk). Here we show that AAF-cmk induces the formation of polyubiquitin-containing accumulations in osteosarcoma and Burkitt's lymphoma cell lines. These accumulations meet many of the landmarks of the aggresomes that form after proteasome inhibition. Using a combination of experiments with chemical inhibitors and interference of gene expression, we show that TPPII inhibition is not responsible for these accumulations. Our evidence suggests that the relevant target(s) is/are in the ubiquitin–proteasome pathway, most likely upstream the proteasome. We obtained evidence supporting this model by inhibition of Hsp90, which also acts upstream the proteasome. Although our data suggest that Hsp90 is not a target of AAF-cmk, its inhibition resulted in accumulations similar to those obtained with AAF-cmk. Therefore, our results question the proposed role for TPPII as a prominent alternative to the proteasome in cellular proteolysis.

Keywords: Abbreviations; AAF-amc; Ala-Ala-Phe-7-amido-4-methylcoumarin; AAF-cmk; Ala-Ala-Phe-chloromethylketone; 17-AAG; 17-(Allylamino)-17-demethoxygeldanamycin; CHX; cycloheximide; GRK2; G protein-coupled receptor kinase 2; TPPII; tripeptidyl peptidase II; Ub; ubiquitin; UPS; ubiquitin–proteasome systemProtein degradation; Proteasome; Tripeptidyl peptidase II; Aggresome; Ubiquitylation

P21-activated kinase 1 stimulates colon cancer cell growth and migration/invasion via ERK- and AKT-dependent pathways by Nhi Huynh; Kevin H. Liu; Graham S. Baldwin; Hong He (pp. 1106-1113).

The p21-activated kinase (PAK) family of serine/threonine kinases plays an important role in cell proliferation, survival and motility, as well as in cell transformation and tumor progression. PAK1 promotes transformation through facilitating the ERK/MAPK pathway and enhances cell migration and survival by stimulating AKT. PAK1 expression increases with the progression of colorectal cancer (CRC). In this study, we have investigated the importance of PAK1 in the biology of colon cancer cells. Reduction of PAK1 expression decreased the activities of ERK and AKT leading to decreased cell proliferation, migration/invasion, and survival. Dual inhibition of ERK and AKT suppressed these cellular processes to levels comparable to those achieved by reduction of PAK1 expression, whereas inactivation of either the ERK or AKT pathway alone partially inhibited cell migration/invasion and survival and had no effect on proliferation. We conclude that PAK1 stimulates colon cancer cell proliferation, migration/invasion, and survival via ERK- and AKT-dependent pathways. These findings establish the central importance of PAK1 in CRC signal transduction and clarify the mechanism by which PAK1 regulates CRC growth and migration. Instead of simultaneously inhibiting both ERK and AKT, the PAK1 convergence point could be an alternative target for CRC therapy.

Keywords: Abbreviations; PAK1; p21-activated kinase 1; CRC; colorectal carcinoma or cancer; MAPK; mitogen-activated protein kinase; MEK; mitogen activated kinase/ERK kinase; ERK; extracellular signal-regulated kinase; PI3K; phosphatidylinositol 3-kinase; VEGF; vascular endothelial growth factorPAK1; Colon cancer; ERK; AKT

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BBA - Molecular Cell Research (v.1803, #9)