Cell Biology Commons^™

Stat-Independent Functions Of Janus Kinases 1 And 2 Are Obligatory For The Postnatal Development Of Mammary Epithelial Ducts, Rayane Dennaoui, Madison N. Wicker, Carson Moen, Michaela Schlederer, Kerry Vistisen, Aleata A. Triplett, Thomas Rülicke, Hallgeir Rui, Lukas Kenner, Emilio Casanova, Kay-Uwe Wagner

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Janus kinases 1 and 2 and STAT transcription factors are critical signaling nodes for numerous growth factors. In the mammary gland, JAK2 and STAT5a/b are essential for alveolar cell differentiation and lactation, but little is known about the cooperative roles of JAKs and STATs before pregnancy. We examined female mice conditionally deficient in JAK1/2 and discovered that both kinases jointly regulate epithelial cell proliferation and ductal morphogenesis. To assess the role of downstream STATs, we generated genetic models co-deficient in STAT3/5a/5b with or without STAT1 or JAK1. Although loss of STAT3/5a/5b leads to a JAK1-dependent upregulation of STAT1, the formation …

The Cdk8 Kinase Module: A Novel Player In The Transcription Of Translation Initiation And Ribosomal Genes, Brittany Friedson, Stephen D Willis, Natalia Shcherbik, Alicia N Campbell, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Survival following stress is dependent upon reprogramming transcription and translation. Communication between these programs following stress is critical for adaptation but is not clearly understood. The Cdk8 kinase module (CKM) of the Mediator complex modulates the transcriptional response to various stresses. Its involvement in regulating translational machinery has yet to be elucidated, highlighting an existing gap in knowledge. Here, we report that the CKM positively regulates a subset of ribosomal protein (RP) and translation initiation factor (TIF)-encoding genes under physiological conditions in Saccharomyces cerevisiae. In mouse embryonic fibroblasts and HCT116 cells, the CKM regulates unique sets of RP and TIF …

Effects Of Cadherin Mediated Contact Normalization On Oncogenic Src Kinase Mediated Gene Expression And Protein Phosphorylation, Rachel E Nicoletto, Cayla J Holdcraft, Ariel C Yin, Edward P Retzbach, Stephanie A Sheehan, Amanda A Greenspan, Christopher M Laugier, Jason Trama, Caifeng Zhao, Haiyan Zheng, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Nontransformed cells form heterotypic cadherin junctions with adjacent transformed cells to inhibit tumor cell growth and motility. Transformed cells must override this form of growth control, called "contact normalization", to invade and metastasize during cancer progression. Heterocellular cadherin junctions between transformed and nontransformed cells are needed for this process. However, specific mechanisms downstream of cadherin signaling have not been clearly elucidated. Here, we utilized a β-catenin reporter construct to determine if contact normalization affects Wnt signaling in transformed cells. β-catenin driven GFP expression in Src transformed mouse embryonic cells was decreased when cultured with cadherin competent nontransformed cells compared to …

Wee1 And Cell Size Control In Fission Yeast By The Protein Kinase Cdr2, Rachel Berg-Murante

Dartmouth College Ph.D Dissertations

The mechanisms that govern cell size have long been topics of study in the field of cell biology. In eukaryotic cells this size control is tied to checkpoints, a set threshold of minimum necessary growth linked to cyclin dependent kinase activity regulation. In the fission yeast Schizosaccharomyces pombe, the Cdk1 regulatory network is conserved, and G2/M represents the major size checkpoint. Prior to mitosis, Cdk1 is inhibited by phosphorylation applied by Wee1 during G2 phase. Once S. pombe cells have satisfied the size checkpoint, Cdk1 is activated through dephosphorylation by Cdc25. Wee1 is a dose-dependent regulator of mitotic entry …

Quantitative Proteomic Strategies To Determine Substrate Specificities Of Phosphoprotein Phosphatases, Hieu Trung Nguyen

Dartmouth College Ph.D Dissertations

Reversible phosphorylation is a crucial regulatory mechanism of cellular signaling pathways. Being the most prevalent post-translational modification (PTM) in the cells, with over 75% of all proteins detected to be phosphorylated, phosphorylation regulates a significant number of important cellular processes that have implications in various diseases. Phosphorylation is carried out by protein kinases, which have been extensively studied. However, the opposite reaction, carried out by protein phosphatases, has lagged significantly, exposing a gap of knowledge that is required to be investigated to delineate the kinase-substrate-phosphatase relationship. Phosphoprotein phosphatase family (PPPs), containing seven members of phospho-Serine (pS) and phospho-Threonine (pT) phosphatases, …

Identification Of Mitotic Phosphatases And Cyclin K As Novel Molecular Targets In Pancreatic Cancer, Yi Xiao

Theses & Dissertations

Pancreatic cancer is a highly lethal disease worldwide. Given the limited effectiveness of current regimens in restricting tumor progression, it is imperative that potential molecular targets be identified to offer valuable insights into alternative therapeutics. By using a phosphate-binding tag (Phos-tag) technique, previous studies have identified several Hippo pathway-related proteins and kinases required for cancer growth or paclitaxel resistance. This work has screened various phosphatases and cyclins/cyclin-dependent kinases (CDKs) as potential cancer targets, but specifically focuses on characterizing the roles of carboxy-terminal domain small phosphatase like 2 (CTDSPL2), apoptosis-stimulating protein of p53-2 (ASPP2), and Cyclin K in pancreatic cancer.

CTDSPL2 …

Proteomic Approaches To Identify Unique And Shared Substrates Among Kinase Family Members, Charles Lincoln Howarth

Dartmouth College Ph.D Dissertations

Protein phosphorylation is a reversible post-translational modification that is a critical component of almost all signaling pathways. Kinases regulate substrate proteins through phosphorylation, and nearly all proteins are phosphorylated to some extent. Crucially, breakdown in phosphorylation signaling is an underlying factor in many diseases, including cancer. Understanding how phosphorylation signaling mediates cellular pathways is crucial for understanding cell biology and human disease.

Targeted protein degradation (TPD) is a strategy to rapidly deplete a protein of interest (POI) and is applicable to any gene that is amenable to CRISPR-Cas9 editing. One TPD approach is the auxin-inducible degron (AID) system, which relies …

Phosphorylation Of Cyclophilin D At Serine 191 Regulates Mitochondrial Permeability Transition Pore Opening And Cell Death After Ischemia-Reperfusion, Stephen Hurst, Fabrice Gonnot, Maya Dia, Claire Crola Da Silva, Ludovic Gomez, Shey-Shing Sheu

Department of Medicine Faculty Papers

The mitochondrial permeability transition pore (mPTP) plays a critical role in the pathogenesis of cardiovascular diseases, including ischemia/reperfusion injury. Although the pore structure is still unresolved, the mechanism through which cyclophilin D (CypD) regulates mPTP opening is the subject of intensive studies. While post-translational modifications of CypD have been shown to modulate pore opening, specific phosphorylation sites of CypD have not yet been identified. We hypothesized here that phosphorylation of CypD on a serine residue controls mPTP opening and subsequent cell death at reperfusion. We combined in silico analysis with in vitro and genetic manipulations to determine potential CypD phosphorylation …

Defining The Role Of Tyrosine Phosphorylation In The Regulation Of Connexin43 In Cardiac Diseases, Li Zheng

Theses & Dissertations

Connexins are integral membrane proteins that oligomerize to form gap junction channels. Ions and small molecules diffuse intercellularly through these channels, allowing individual cellular events to synchronize into the functional response of an entire organ. Gap junction channels composed of Connexin43 (Cx43) mediate electrical coupling and impulse propagation in the normal working myocardium. In the failing heart, Cx43 remodeling (decreased expression, altered phosphorylation state, loss at intercalated discs, and increased presence at lateral membranes) contributes to rhythm disturbances and contractile dysfunction. While there is considerable information regarding key interactions of Cx43 in the regulation of gap junction channels, unfortunately, the …

A Novel Switch-Like Function Of Delta-Catenin In Dendrite Development, Ryan Baumert

Dissertations and Theses (Open Access)

The formation of neuronal networks in the brain is tightly regulated, and dependent on the morphology of dendrites, the branch-like signal-receiving structures extending from neurons. Disruptions in dendrite development, or dendritogenesis, can lead to the atypical neuronal connectivity associated with multiple neurodevelopmental diseases. My research addresses molecular processes that underlie dendritogenesis via analysis of a pair of novel interactions involving the protein delta-catenin.

In neurons, delta-catenin localizes to dendrites and synapses, where it functions in their development and maintenance. Structurally, delta-catenin possesses a central Armadillo domain and a C-terminal PDZ-binding motif. This motif associates with PDZ domain-containing proteins, and is …

Induction Of Ampk Activation By N,N'-Diarylurea Fnd-4b Decreases Growth And Increases Apoptosis In Triple Negative And Estrogen-Receptor Positive Breast Cancers, Jeremy Johnson, Piotr G. Rychahou, Vitaliy M. Sviripa, Heidi L. Weiss, Chunming Liu, David S. Watt, B. Mark Evers

Markey Cancer Center Faculty Publications

Purpose

Triple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC.

Materials and methods

(i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. …

P53 Phosphomimetics Preserve Transient Secondary Structure But Reduce Binding To Mdm2 And Mdmx, Robin Levy, Emily Gregory, Wade Borcherds, Gary W. Daughdrill

Molecular Biosciences Faculty Publications

The disordered p53 transactivation domain (p53TAD) contains specific levels of transient helical secondary structure that are necessary for its binding to the negative regulators, mouse double minute 2 (Mdm2) and MdmX. The interactions of p53 with Mdm2 and MdmX are also modulated by posttranslational modifications (PTMs) of p53TAD including phosphorylation at S15, T18 and S20 that inhibits p53-Mdm2 binding. It is unclear whether the levels of transient secondary structure in p53TAD are changed by phosphorylation or other PTMs. We used phosphomimetic mutants to determine if adding a negative charge at positions 15 and 18 has any effect on the transient …

Intra- And Inter-Molecular Signaling In A Cardiac Connexin: Role Of Cytoplasmic Domain Dimerization And Phosphorylation, Andrew J. Trease

Theses & Dissertations

As critical mediators of cell-to-cell communication, gap junctions (GJs) are comprised of membrane channels that directly link the cytoplasm of adjacent coupled cells thereby allowing for the passage of ions, small metabolites, and secondary messengers. Each channel is formed by the apposition of two connexons from adjacent cells, each composed of six connexin (Cx) proteins. Each GJ channel functions to promote signal propagation and synchronization of cells and tissues in organs. Furthermore, GJs are essential for proper propagation of cardiac action potentials from one cell to the next, leading to the coordinated contraction and relaxation of heart muscle powering circulation. …

Structural And Functional Characterization Of Hyper-Phosphorylated Grk5 Protein Expressed From E. Coli, Joseph M. Krampen, John Tesmer, Qiuyan Chen

The Summer Undergraduate Research Fellowship (SURF) Symposium

G protein-coupled receptor (GPCR) kinases (GRKs) are proteins in the cell responsible for regulating GPCRs located on the cell membrane. GRKs regulate active GPCRs by phosphorylating them at certain sites which causes them to stop normal signaling on the membrane. This ultimately affects how the cell responds to its environment. GRK5 is a kinase of particular interest due to its involvement in the pathology of diseases such as cardiac failure, cancers, and diabetes. Understanding the structure and function of GRK5 is essential for discovering ways to manipulate its behavior with these diseases, but not much is known about how GRK5 …

The Role Of Mapk And Scf In The Destruction Of Med13 In Cyclin C Mediated Cell Death, David C Stieg, Stephen D Willis, Joseph Scuorzo, Mia Song, Vidyaramanan Ganesan, Randy Strich, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

In response to stress, the yeast¹ and mammalian² cyclin C translocate from the nucleus to the cytoplasm, where it associates with the GTPase Drp1/Dnm1 to drive mitochondrial fragmentation and apoptosis. Therefore, the decision to release cyclin C represents a key life or death decision. In unstressed cells, the cyclin C‐Cdk8 kinase regulates transcription by associating with the Mediator of RNA polymerase II. We previously reported that the Mediator component Med13 anchors cyclin C in the nucleus³. Loss of Med13 function leads to constitutive cytoplasmic localization of cyclin C, resulting in fragmented mitochondria, hypersensitivity to stress and …

Phopsphorylation And Ubiquitin Modification At Dna Damage Sites In Response To Double-Strand Breaks, Atanu Paul

Dissertations and Theses (Open Access)

Genomes of all organisms are continuously damaged by numerous exogenous and endogenous sources leading to different kinds of DNA lesions, which if not repaired efficiently may trigger wide-scale genomic instability, a hallmark of cancer development. To overcome this, cells have evolved a sophisticated sensory network called the DNA damage response (DDR) comprised of a large number of distinct protein complexes categorized as sensor, mediator, transducer and effector proteins that amplify the DNA damage signal and activate cell cycle checkpoint to initiate DNA repair or trigger apoptosis where the defect is beyond repair. This intricate signaling pathway is tightly regulated by …

Defining The Role Of Phosphorylation And Dephosphorylation In The Regulation Of Gap Junction Proteins, Hanjun Li

Theses & Dissertations

Gap junctions are intercellular channels that permit the free passage of ions, small metabolites, and signaling molecules between neighboring cells. In the diseased human heart, altered ventricular gap junction organization and connexin expression (i.e., remodeling) are key contributors to rhythm disturbances and contractile dysfunction. Connexin43 (Cx43) is the dominant gap junction protein isoform in the ventricle which is under tight regulation by serine/tyrosine phosphorylation. Phosphorylation and dephosphorylation regulate many aspects of Cx43 function including trafficking, assembly and disassembly, electrical and metabolic coupling at the plaque, as well as to modulate the interaction with other proteins.

Serine phosphorylation has long been …

Analysis Of The Candida Albicans Phosphoproteome, S. D. Willger, Z. Liu, R. A. Olarte, M. E. Adamo, J E. Stajich, L C. Myers, A N. Kettenbach, D A. Hogan

Dartmouth Scholarship

Candida albicans is an important human fungal pathogen in both immunocompetent and immunocompromised individuals. C. albicans regulation has been studied in many contexts, including morphological transitions, mating competence, biofilm forma- tion, stress resistance, and cell wall synthesis. Analysis of kinase- and phosphatase-deficient mutants has made it clear that pro- tein phosphorylation plays an important role in the regulation of these pathways. In this study, to further our understanding of phosphorylation in C. albicans regulation, we performed a deep analysis of the phosphoproteome in C. albicans. We identified 19,590 unique peptides that corresponded to 15,906 unique phosphosites on 2,896 proteins. The …

Using A Novel Multiplexing Method To Track Cell Populations And Cytodifferentiation During Development Of The Submandibular Salivary Gland, Charles Thomas Manhardt

Legacy Theses & Dissertations (2009 - 2024)

The development of submandibular salivary glands is complex and requires coordination of specific signaling events. Submandibular salivary glands originate as an epithelial invagination into the adjacent mesenchyme that leads to a single stalk and end bud; this end bud will go through a clefting process. Numerous rounds of clefting will lead to a fully developed salivary gland by this process, which is known as branching morphogenesis. As the gland undergoes morphogenesis, specific cues leading to differentiation of multiple cell types and even epithelial sub classes are required. By the later stages of development the glands are fully innervated, have an …

Altered Connexin 43 Expression Underlies Age-Dependent Decrease Of Regulatory T Cell Suppressor Function In Nonobese Diabetic Mice, Michel Kuczma, Cong-Yi Wang, Leszek Ignatowicz, Robert Gourdi, Piotr Kraj

Biological Sciences Faculty Publications

Type 1 diabetes is one of the most extensively studied autoimmune diseases, but the cellular and molecular mechanisms leading to T cell–mediated destruction of insulin-producing β cells are still not well understood. In this study, we show that regulatory T cells (T_regs) in NOD mice undergo age-dependent loss of suppressor functions exacerbated by the decreased ability of activated effector T cells to upregulate Foxp3 and generate T_regs in the peripheral organs. This age-dependent loss is associated with reduced intercellular communication mediated by gap junctions, which is caused by impaired upregulation and decreased expression of connexin 43. Regulatory …

Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi

Dissertations and Theses (Open Access)

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser³³⁸ and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser³³⁸ phosphorylation …

Analysis Of The Regulation And Function Of Cip2a To Identify Candidate Biomarkers For Prostate Cancer, Diana Savoly

Graduate School of Biomedical Sciences Theses and Dissertations

Protein Phosphatase 2A (PP2A) is a tumor suppressor involved in the regulation of several signaling pathways and the cell cycle. PP2A becomes inactivated by several inhibitors, including Cancerous Inhibitor of PP2A (CIP2A). CIP2A has been identified as an oncogene, which is over-expressed in cancers and inhibits PP2A through direct interaction. CIP2A is recognized as a biomarker for cancer; however, it is not cancer-specific. Therefore, we identified and examined the use of CIP2A-regulated proteins as potential biomarkers in prostate cancer to better diagnose prostate cancer in patients. Currently, Prostate Specific Antigen (PSA) is widely used to detect prostate cancer; however, it …

Protein 14-3-3 (Ywha) Isoforms And Their Roles In Regulating Mouse Oocyte Maturation, Santanu De

Biology Faculty Books and Book Chapters

The 14-3-3 (YWHA) is a highly conserved, ubiquitously expressed protein family regulating important cellular processes including cell cycle. This work, for the first time, explored the differential expression and roles of 14-3-3 isoforms during mouse oocyte maturation.

All seven mammalian 14-3-3 isoforms were identified in mouse eggs and ovarian follicular cells including oocytes, by Western blotting. Immunocytochemical and immunohistochemical staining confirmed the presence of all 14-3-3 isoforms in oocytes, eggs and ovarian follicles with characteristic similarities and differences in their distributions.

Mammalian oocytes are arrested at meiosis prophase I by an inhibitory phosphorylation on Cyclin-Dependent Kinase I (CDK1), released by …

Phosphorylation Of Histone Deacetylase 6 Within Its C-Terminal Region By Extracellular Signal Regulated Kinase 1, Kendra Allana Williams

USF Tampa Graduate Theses and Dissertations

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The Human Phosphotyrosine Signaling Network: Evolution And Hotspots Of Hijacking In Cancer., Lei Li, Chabane Tibiche, Cong Fu, Tomonori Kaneko, Michael F. Moran, Martin Schiller, Shawn Shun-Cheng Li, Edwin Wang

Life Sciences Faculty Research

Phosphotyrosine (pTyr) signaling, which plays a central role in cell-cell and cell-environment interactions, has been considered to be an evolutionary innovation in multicellular metazoans. However, neither the emergence nor the evolution of the human pTyr signaling system is currently understood. Tyrosine kinase (TK) circuits, each of which consists of a TK writer, a kinase substrate, and a related reader, such as Src homology (SH) 2 domains and pTyr-binding (PTB) domains, comprise the core machinery of the pTyr signaling network. In this study, we analyzed the evolutionary trajectories of 583 literature-derived and 50,000 computationally predicted human TK circuits in 19 representative …

The Role Of Argininosuccinate Synthase Serine 328 Phosphorylation In Nitric Oxide Production, Ricci Haines

USF Tampa Graduate Theses and Dissertations

Until recently, the main mechanism of argininosuccinate synthase (AS) regulation was described to exist mainly at the level of transcription. Transcriptional regulation of AS has been shown to be coordinate with eNOS in response to shear stress, hypoxia, tumor necrosis factor á (TNF-á), and PPAR ã agonist troglitizone. However, it is now understood that one level of NO regulation is cellular control of arginine availability to eNOS via post-translational modifications of AS such as phosphorylation. The purpose of this investigation was to determine under what conditions AS is phosphorylated at S328, identify the pathway that AS phosphorylation at S328 plays …

Phosphorylation Of The Glycine Transporter 1, Javier Vargas Medrano

Open Access Theses & Dissertations

The extracellular levels of the neurotransmitter glycine in the brain are tightly regulated by the high-affinity glycine transporter 1 (GlyT1) and the clearance of glycine depends on its rate of transport and the levels of cell surface GlyT1. Over the past years, it has been shown that PKC activation diminishes the activity and promoted phosphorylation of several neurotransmitter transporters including the dopamine, serotonin and norepinephrine transporters however, its role is unknown for the glycine transporter. To get insights into the role of PKC activation on GlyT1 regulation, we used three N-terminus GlyT1 isoforms stably expressed in porcine aortic endothelial (PAE) …

Mtorc1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis Via Increased Hexokinase Ii And Glut1 Expression, Sustained Mcl-1 Expression, And Glycogen Synthase Kinase 3Β Inhibition, Prashanth T. Bhaskar, Veronique Nogueira, Krushna C. Patra, Sang-Min Jeon, Youngkyu Park, R. Brooks Robey, Nissim Hay

Dartmouth Scholarship

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed to both …

Analysis Of The Phosphorylated Forms Of Protein Kinase R, Christine Quartararo

Honors Scholar Theses

Protein Kinase R (PKR) is induced by interferon and activated by dsRNA. Subsequent autophosphorylation and phosphorylation of eIF2alpha inhibits viral replication. In the latent state PKR exists as an unphosphorylated monomer. Work in the Cole laboratory has shown two additional states, a phosphorylated monomeric state (pPKRm) and a phosphorylated dimeric state (pPKRd). RNA serves as a scaffold bringing two PKRs together allowing dimerization and autophosphorylation to occur. The contribution of each state to the function of PKR remains unclear. Western blots were performed to examine the phosphorylation states of the essential residues,

T446 and T451. Activity assays have shown activation …

Alterations In Human B Cell Calcium Homeostasis By Polycyclic Aromatic Hydrocarbons: Possible Associations With Cytochrome P450 Metabolism And Increased Tyrosine Phosphorylation, Barbara J. Mounho

Pharmaceutical Sciences ETDs

Polycyclic aromatic hydrocarbons (PAHs), are known immunotoxicants in animals, and are suspect toxins to the human immune system. The mechanism(s), however, by which PAHs exert immunosuppression have not been fully elucidated. Previous studies conducted in our laboratory have shown that PAHs, such as 7,12-dimethylbenz(a)- anthracene (DMB A) and benzo(a)pyrene (BaP) may exert their immunotoxic effects by altering intracellular calcium (Ca2+) homeostasis in lymphocytes. Intracellular Ca2+ is an important second messenger in the immune response, and the mobilization of Ca2+ is critical in the transduction of intracellular signals from the plasma membrane to the nucleus. The overall objective of this project …