Tensin: A potential link between the cytoskeleton and signal transduction

Cytoskeletal proteins provide the structural foundation that allows cells to exist in a highly organized manner. Recent evidence suggests that certain cytoskeletal proteins not only maintain structural integrity, but might also be associated with signal transduction and suppression of tumorigenesis. Since the time of the discovery of tensin, a fair amount of data has been gathered which supports the notion that tensin is one such protein possessing these characteristics. In this review, we discuss recent studies that: (1) elucidate a role for tensin in maintenance of cellular structure and signal transduction; (2) implicate tensin as the anchor for actin filaments at the focal adhesion; (3) describe the phosphorylation of tensin; (4) describe potential targets for its Src homology region 2 domain; (5) describe the association between tensin and the nuclear protein p130; and (6) demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential.     

Lymphatic system: a vital link between metabolic syndrome and inflammation

Metabolic syndrome is defined by a cluster of different metabolic risk factors that include overall and central obesity, elevated fasting glucose levels, dyslipidemia, hypertension, and intimal atherogenesis. Metabolic syndrome leads to increased risk for the development of type 2 diabetes and cardiovascular disease (e.g., heart disease and stroke). The exacerbated progression of metabolic syndrome to cardiovascular disease has lead to intense study of the physiological ramifications of metabolic syndrome on the blood vasculature. These studies have particularly focused on the signaling and architectural alterations that manifest in hypertension and atherosclerosis. However, despite the overlap of metabolic syndrome pathology with lymphatic function, tangent effects on the lymphatic system have not been extensively documented. In this review, we discuss the current status of metabolic syndrome and provide evidence for, and the remaining challenges in studying, the connections among the lymphatic system, lipid transport, obesity, insulin resistance, and general inflammation.     

TonB protein and energy transduction between membranes

TonB protein couples cytoplasmic membrane electrochemical potential to active transport of iron-siderophore complexes and vitamin B12 through high-affinity outer membrane receptors of Gram-negative bacteria. The mechanism of energy transduction remains to be determined, but important concepts have already begun to emerge. Consistent with its function, TonB is anchored in the cytoplasmic membrane by its uncleaved amino terminus while largely occupying the periplasm. Both the connection to the cytoplasmic membrane and the amino acid sequences of the anchor are essential for activity. TonB directly associates with a number of envelope proteins, among them the outer membrane receptors and cytoplasmic membrane protein ExbB. ExbB and TonB interact through their respective transmembrane domains. ExbB is proposed to recycle TonB to an active conformation following energy transduction to the outer membrane. TonB most likely associates with the outer membrane receptors through its carboxy terminus, which is required for function. In contrast, the novel prolinerich region of TonB can be deleted without affecting function. A model that incorporates this information, as well as tempered speculation, is presented.     

A potential link between dorsomedial hypothalamic nucleus NPY and energy balance

The function of dorsomedial hypothalamic neuropeptide Y (NPY) in energy balance has largely been restricted to lactation-induced hyperphagia. In this issue, Chao et?al. (2011) expand this role to include inhibition of both brown fat thermogenesis and conversion of white-to-brown adipocytes in a white fat depot, resulting in reduced energy expenditure.     

APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment

Signals generated in response to extracellular stimuli at the plasma membrane are transmitted through cytoplasmic transduction cascades to the nucleus. We report the identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogenesis. This pathway operates via APPL1 and APPL2, two Rab5 effectors, which reside on a subpopulation of endosomes. In response to extracellular stimuli such as EGF and oxidative stress, APPL1 translocates from the membranes to the nucleus where it interacts with the nucleosome remodeling and histone deacetylase multiprotein complex NuRD/MeCP1, an established regulator of chromatin structure and gene expression. Both APPL1 and APPL2 are essential for cell proliferation and their function requires Rab5 binding. Our findings identify an endosomal compartment bearing Rab5 and APPL proteins as an intermediate in signaling between the plasma membrane and the nucleus.     

S100 proteins modulate protein phosphatase 5 function: a link between CA2+ signal transduction and protein dephosphorylation

PP5 is a unique member of serine/threonine phosphatases comprising a regulatory tetratricopeptide repeat (TPR) domain and functions in signaling pathways that control many cellular responses. We reported previously that Ca(2+)/S100 proteins directly associate with several TPR-containing proteins and lead to dissociate the interactions of TPR proteins with their client proteins. Here, we identified protein phosphatase 5 (PP5) as a novel target of S100 proteins. In vitro binding studies demonstrated that S100A1, S100A2, S100A6, and S100B proteins specifically interact with PP5-TPR and inhibited the PP5-Hsp90 interaction. In addition, the S100 proteins activate PP5 by using a synthetic phosphopeptide and a physiological protein substrate, Tau. Overexpression of S100A1 in COS-7 cells induced dephosphorylation of Tau. However, S100A1 and permanently active S100P inhibited the apoptosis signal-regulating kinase 1 (ASK1) and PP5 interaction, resulting the inhibition of dephosphorylation of phospho-ASK1 by PP5. The association of the S100 proteins with PP5 provides a Ca(2+)-dependent regulatory mechanism for the phosphorylation status of intracellular proteins through the regulation of PP5 enzymatic activity or PP5-client protein interaction.     

TonB-dependent energy transduction between outer and cytoplasmic membranes

The TonB system of Escherichia coli (and most other Gram-negative bacteria) is distinguished by its importance to iron acquisition, its contribution to bacterial pathogenesis, and a unique and mysterious mechanism of action. This system somehow gathers the potential energy of the cytoplasmic membrane (CM) proton gradient and delivers it to active transporters in the outer membrane (OM). Our understanding of this system is confounded by the challenge of reconciling often contradictory in vivo and in vitro studies that are presented in this review.     

The BK channel: a vital link between cellular calcium and electrical signaling

Large-conductance Ca²⁺-activated K⁺ channels (BK channels) constitute an key physiological link between cellular Ca²⁺ signaling and electrical signaling at the plasma membrane. Thus these channels are critical to the control of action potential firing and neurotransmitter release in several types of neurons, as well as the dynamic control of smooth muscle tone in resistance arteries, airway, and bladder. Recent advances in our understanding of K⁺ channel structure and function have led to new insight toward the molecular mechanisms of opening and closing (gating) of these channels. Here we will focus on mechanisms of BK channel gating by Ca²⁺, transmembrane voltage, and auxiliary subunit proteins.     

TPA-induced signal transduction: a link between PKC and EGFR signaling modulates the assembly of intercellular junctions in Caco-2 cells

Recent studies suggest that signal transduction may have an important role in the development and regulation of the metastatic phenotype. Here, we investigated the role of the epidermal growth factor receptor (EGFR), and protein kinase C (PKC), in the process of reassembly of cadherin-dependent cell-cell adhesion of Caco-2 cells. We used chemical activation of PKC and EGFR with 12- O-tetradecanoylphorbol-13-acetate (TPA), a tumor-promoting agent, pretreatment with protein kinase inhibitors and subcellular fractionation to analyze the effect of the phorbol ester on the redistribution of junctional proteins. Transepithelial resistance (TER), electron microscopy and immunofluorescence analyses were also carried out. Activation with TPA resulted in disassembly of adherens junctions (AJs), but the tight junction (TJ) structure and function remained unaltered. TPA affected E-cadherin levels. In Caco-2 cells at day 2 of culture, when most E-cadherin is not associated with the cytoskeleton, a decrease in the level of this protein was observed as soon as 6 h after TPA addition. However, at day 5 of culture, the major effect observed after 6 h of treatment was a translocation of the protein from the Triton-insoluble to the -soluble fraction. On the other hand, TPA did not significantly affect the E-cadherin-associated proteins alpha and beta-catenins. Potent specific EGFR inhibitors, such as PD153035 and Tyrphostin 25, as well as Calphostin C, an inhibitor of PKC, significantly blocked the effect of TPA on AJs. Furthermore, inhibition of the TPA effect by the PD98059 MAPK inhibitor suggests that activation of this kinase was the final event in the modulation of cadherin-dependent cell-cell adhesion. Pretreatment of cell monolayers with Calphostin C before EGF treatment, one of the ligands of EGFR, blocked the redistribution of E-cadherin caused by EGF. Based on these results, we conclude that both EGFR and PKC activation are involved in TPA-induced cell signaling for modulation of cadherin-dependent cell-cell adhesion and cell shape in Caco-2 cells.     

Microtubules and signal transduction

Although molecular components of signal transduction pathways are rapidly being identified, how elements of these pathways are positioned spatially and how signals traverse the intracellular environment from the cell surface to the nucleus or to other cytoplasmic targets are not well understood. The discovery of signaling molecules that interact with microtubules (MTs), as well as the multiple effects on signaling pathways of drugs that destabilize or hyperstabilize MTs, indicate that MTs are likely to be critical to the spatial organization of signal transduction. MTs themselves are also affected by signaling pathways and this may contribute to the transmission of signals to downstream targets.     

Oxygen signal transduction

Although manifestations of O2 adaptation have long been examined, only now are biochemical mechanisms of O2 regulation beginning to be understood. This article comments on the current state of knowledge about proteins that function as direct sensors of molecular oxygen and makes predictions about as yet undiscovered sensors.