The black box illuminated: signals and signaling.

Unraveling the signaling pathways that transmit information from the cell surface to the nucleus has been a major accomplishment of modern cell and molecular biology. The benefit to humans is seen in the multitude of new therapeutics based on the illumination of these pathways. Although considerable insight has been gained in understanding homeostatic and pathological signaling in the epidermis and other skin compartments, the translation into therapy has been lacking. This review will outline advances made in understanding fundamental signaling in several of the most prominent pathways that control cutaneous development, cell-fate decisions, and keratinocyte growth and differentiation with the anticipation that this insight will contribute to new treatments for troubling skin diseases.

[1]  M. Karin,et al.  IKKα controls formation of the epidermis independently of NF-κB , 2001, Nature.

[2]  S. Nishikawa,et al.  Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells , 2006, The Journal of cell biology.

[3]  Raphael Kopan,et al.  The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism , 2009, Cell.

[4]  D. Roop,et al.  Identification of a calcium-inducible, epidermal-specific regulatory element in the 3'-flanking region of the human keratin 1 gene. , 1993, The Journal of investigative dermatology.

[5]  S. Ogbourne,et al.  PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: Results of a randomized, double‐blind, vehicle‐controlled, multicentre, phase IIa study , 2009, The Australasian journal of dermatology.

[6]  H. Kitano,et al.  A comprehensive pathway map of epidermal growth factor receptor signaling , 2005, Molecular systems biology.

[7]  T. Kataoka,et al.  Multiple roles of phosphoinositide-specific phospholipase C isozymes. , 2008, BMB reports.

[8]  F. Marks,et al.  Loss of Protein Kinase Cδ from Human HaCaT Keratinocytes upon Ras Transfection Is Mediated by TGFα , 1995 .

[9]  R. Perez-soler,et al.  Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  A. Ullrich,et al.  Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. , 1995, The EMBO journal.

[11]  Z. Szallasi,et al.  Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[12]  D. Clapham,et al.  TRP Channel Regulates EGFR Signaling in Hair Morphogenesis and Skin Barrier Formation , 2010, Cell.

[13]  S. Yuspa,et al.  Inducible cutaneous inflammation reveals a protumorigenic role for keratinocyte CXCR2 in skin carcinogenesis. , 2009, Cancer research.

[14]  S. Rhee,et al.  Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes. , 1993, The Journal of investigative dermatology.

[15]  Freddy Radtke,et al.  Multiple roles of Notch signaling in the regulation of epidermal development. , 2008, Developmental cell.

[16]  F. Khanim,et al.  PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. , 2005, Blood.

[17]  Freddy Radtke,et al.  Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation , 2001, The EMBO journal.

[18]  Luowei Li,et al.  Inhibitors of the intracellular Ca(2+)-ATPase in cultured mouse keratinocytes reveal components of terminal differentiation that are regulated by distinct intracellular Ca2+ compartments. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[19]  E Gratton,et al.  The epidermal Ca(2+) gradient: Measurement using the phasor representation of fluorescent lifetime imaging. , 2010, Biophysical journal.

[20]  D. Bikle,et al.  The Recruitment of Phosphatidylinositol 3-Kinase to the E-cadherin-Catenin Complex at the Plasma Membrane Is Required for Calcium-induced Phospholipase C-γ1 Activation and Human Keratinocyte Differentiation* , 2007, Journal of Biological Chemistry.

[21]  C. Woodworth,et al.  Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment , 2005, Molecular Cancer Therapeutics.

[22]  Andrew Lee,et al.  The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature. , 2010, Cancer research.

[23]  P M Steinert,et al.  Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro , 1989, The Journal of cell biology.

[24]  T. Maududi,et al.  The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas , 2006, Oncogene.

[25]  T. Kuroki,et al.  Protein kinase C eta (PKC eta): its involvement in keratinocyte differentiation. , 2002, Journal of biochemistry.

[26]  Y. Nishizuka.  The role of protein kinase C in cell surface signal transduction and tumour promotion , 1984, Nature.

[27]  Hui Zheng,et al.  Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Rüdiger Klein,et al.  Mig6 is a negative regulator of EGF receptor–mediated skin morphogenesis and tumor formation , 2006, Nature Medicine.

[29]  D. Mochly‐Rosen,et al.  Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function. , 2007, Pharmacological research.

[30]  G. Girolomoni,et al.  Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. , 2003, The American journal of pathology.

[31]  Y. Hanakawa,et al.  Mechanism of thymus- and activation-regulated chemokine (TARC)/CCL17 production and its modulation by roxithromycin. , 2005, Journal of Investigative Dermatology.

[32]  F. Watt,et al.  Stimulation of human epidermal differentiation by Delta–Notch signalling at the boundaries of stem-cell clusters , 2000, Current Biology.

[33]  E. A. Reece,et al.  PKC-delta and -eta, MEKK-1, MEK-6, MEK-3, and p38-delta are essential mediators of the response of normal human epidermal keratinocytes to differentiating agents. , 2010, The Journal of investigative dermatology.

[34]  T. Magnuson,et al.  Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. , 1997, The American journal of pathology.

[35]  S. Yuspa,et al.  Protein Kinase Cα-Mediated Chemotaxis of Neutrophils Requires NF-κB Activity but Is Independent of TNFα Signaling in Mouse Skin In Vivo1 , 2005, The Journal of Immunology.

[36]  Hans Clevers,et al.  Notch1 functions as a tumor suppressor in mouse skin , 2003, Nature Genetics.

[37]  D. Threadgill,et al.  EGFR regulates the expression of keratinocyte-derived granulocyte/macrophage colony-stimulating factor in vitro and in vivo. , 2010, The Journal of investigative dermatology.

[38]  S. Ogawa,et al.  Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis , 2007, Pigment cell & melanoma research.

[39]  T. Cartee,et al.  Epidermal Growth Factor Receptor Inhibition Augments the Expression of MHC Class I and II Genes , 2011, Clinical Cancer Research.

[40]  J. Putney.  Capacitative calcium entry: from concept to molecules , 2009, Immunological reviews.

[41]  Raphael Kopan,et al.  SnapShot: Notch Signaling Pathway , 2007, Cell.

[42]  Kenneth R Feingold,et al.  Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms. , 2002, The Journal of investigative dermatology.

[43]  H. Wen,et al.  Moderate Reduction of γ-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities , 2007, The Journal of Neuroscience.

[44]  Peter J Parker,et al.  PKC at a glance , 2004, Journal of Cell Science.

[45]  T. Magnuson,et al.  Activation of the Epidermal Growth Factor Receptor Signal Transduction Pathway Stimulates Tyrosine Phosphorylation of Protein Kinase C (*) , 1996, The Journal of Biological Chemistry.

[46]  B. Spiegelman,et al.  Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters , 1997, Oncogene.

[47]  Karen Holbrook,et al.  Calcium regulation of growth and differentiation of mouse epidermal cells in culture , 1980, Cell.

[48]  D. Wheeler,et al.  Overexpression of Protein Kinase C- (cid:1) in the Mouse Epidermis Leads to a Spontaneous Myeloproliferative-Like Disease , 2004 .

[49]  M. Lacouture.  Mechanisms of cutaneous toxicities to EGFR inhibitors , 2006, Nature Reviews Cancer.

[50]  B. Nürnberg,et al.  Tumor immune escape by the loss of homeostatic chemokine expression , 2007, Proceedings of the National Academy of Sciences.

[51]  S. Yuspa,et al.  Early signals for keratinocyte differentiation: role of Ca2+-mediated inositol lipid metabolism in normal and neoplastic epidermal cells. , 1988, Carcinogenesis.

[52]  V. Grachtchouk,et al.  Receptor-type Protein-tyrosine Phosphatase-κ Regulates Epidermal Growth Factor Receptor Function* , 2005, Journal of Biological Chemistry.

[53]  J. Zou,et al.  Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. , 2000, Cancer research.

[54]  D. Bikle,et al.  Inactivation of the Calcium Sensing Receptor Inhibits E-cadherin-mediated Cell-Cell Adhesion and Calcium-induced Differentiation in Human Epidermal Keratinocytes* , 2008, Journal of Biological Chemistry.

[55]  Elaine Fuchs,et al.  Canonical notch signaling functions as a commitment switch in the epidermal lineage. , 2006, Genes & development.

[56]  Raphael Kopan,et al.  Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. , 2009, Cancer cell.

[57]  A. Hovnanian,et al.  Darier disease : a disease model of impaired calcium homeostasis in the skin. , 2011, Biochimica et biophysica acta.

[58]  D. Wheeler,et al.  Protein Kinase C-ε Transgenic Mice: A Unique Model for Metastatic Squamous Cell Carcinoma , 2001 .

[59]  E. Wagner,et al.  c-Jun regulates eyelid closure and skin tumor development through EGFR signaling. , 2003, Developmental cell.

[60]  Cathrin Brisken,et al.  Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis. , 2010, Genes & development.

[61]  A. Borczuk,et al.  Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. , 2010, Carcinogenesis.

[62]  M. Mann,et al.  Phosphotyrosine interactome of the ErbB-receptor kinase family , 2005, Molecular systems biology.

[63]  A. Sorkin,et al.  Endocytosis and intracellular trafficking of ErbBs. , 2009, Experimental cell research.

[64]  G. Girolomoni,et al.  ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation1 , 2005, The Journal of Immunology.

[65]  K. Tsukinoki,et al.  Restoration of BRAK / CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma , 2009, Cancer science.

[66]  R. Paus,et al.  Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology. , 2009, The Journal of investigative dermatology.

[67]  M. Denda,et al.  Expression of voltage‐gated calcium channel subunit α1C in epidermal keratinocytes and effects of agonist and antagonists of the channel on skin barrier homeostasis , 2006, Experimental dermatology.

[68]  C. Tseng,et al.  Transgenic mice overexpressing protein kinase Cdelta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. , 1999, Cancer research.

[69]  Luowei Li,et al.  Chelation of intracellular Ca2+ inhibits murine keratinocyte differentiation in vitro , 1995, Journal of cellular physiology.

[70]  S. Yuspa,et al.  Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta. , 1993, The Journal of biological chemistry.

[71]  Raphael Kopan,et al.  gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. , 2004, Developmental cell.

[72]  G. Schultz,et al.  Ca2+-controlled competitive diacylglycerol binding of protein kinase C isoenzymes in living cells , 2002, The Journal of cell biology.

[73]  S. Yuspa,et al.  Ultraviolet light irradiation increases cellular diacylglycerol and induces translocation of diacylglycerol kinase in murine keratinocytes. , 1992, The Journal of investigative dermatology.

[74]  H. Llewelyn Roderick,et al.  Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival , 2008, Nature Reviews Cancer.

[75]  R. Laursen,et al.  Protein Kinase C-β Activates Tyrosinase by Phosphorylating Serine Residues in Its Cytoplasmic Domain* , 1999, The Journal of Biological Chemistry.

[76]  L. Komuves,et al.  The role of the calcium-sensing receptor in epidermal differentiation. , 2004, Cell calcium.

[77]  Raphael Kopan,et al.  Murine vibrissae cultured in serum-free medium reinitiate anagen. , 2008, The Journal of investigative dermatology.

[78]  P. Khavari,et al.  Erk1/2 MAP kinases are required for epidermal G2/M progression , 2009, The Journal of cell biology.

[79]  G. Dotto.  Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis. , 2011, Cancer research.

[80]  E Lee,et al.  Changes in inositol phosphate metabolism are associated with terminal differentiation and neoplasia in mouse keratinocytes. , 1991, Carcinogenesis.

[81]  D. Edwards,et al.  The ADAM metalloproteinases , 2008, Molecular Aspects of Medicine.

[82]  M. Gessler,et al.  Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers. , 2000, Development.

[83]  T. Soderling,et al.  Analysis of CaM-kinase signaling in cells. , 2011, Cell calcium.

[84]  M. Aziz,et al.  Protein kinase C epsilon, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. , 2007, Cancer research.

[85]  E. Wolf,et al.  Beyond Wavy Hairs The Epidermal Growth Factor Receptor and Its Ligands in Skin Biology and Pathology , 2010 .

[86]  B. Gilchrest,et al.  Topical application of a protein kinase C inhibitor reduces skin and hair pigmentation. , 2004, The Journal of investigative dermatology.

[87]  Raphael Kopan,et al.  Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes , 2007, Development.

[88]  J. Lapins,et al.  Incidence of cancer among patients with hidradenitis suppurativa. , 2001, Archives of dermatology.

[89]  M. Denning.  Epidermal keratinocytes: regulation of multiple cell phenotypes by multiple protein kinase C isoforms. , 2004, The international journal of biochemistry & cell biology.

[90]  Baoxi Wang,et al.  γ-Secretase Gene Mutations in Familial Acne Inversa , 2010, Science.

[91]  D. Dixon,et al.  Keratinocyte K+ channels mediate Ca2+-induced differentiation. , 1997, The Journal of investigative dermatology.

[92]  Jennifer Y. Zhang,et al.  NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia , 2003, Nature.

[93]  J. Black,et al.  Identification of Two Distinct Pathways of Protein Kinase Cα Down-regulation in Intestinal Epithelial Cells* , 2004, Journal of Biological Chemistry.

[94]  J. Voorhees,et al.  Epidermal Growth Factor Receptor-dependent, NF-κB-independent Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Inhibits Ultraviolet Irradiation-induced Caspases-3, -8, and -9 in Human Keratinocytes* , 2003, Journal of Biological Chemistry.

[95]  A. Monaco,et al.  Hailey–Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump , 2000 .

[96]  W. Leonard,et al.  Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin , 2010, PloS one.

[97]  C. Liebmann.  EGF receptor activation by GPCRs: An universal pathway reveals different versions , 2011, Molecular and Cellular Endocrinology.

[98]  E. Gratton,et al.  Major translocation of calcium upon epidermal barrier insult: imaging and quantification via FLIM/Fourier vector analysis , 2011, Archives of Dermatological Research.

[99]  P. Grigsby,et al.  Notch-Deficient Skin Induces a Lethal Systemic B-Lymphoproliferative Disorder by Secreting TSLP, a Sentinel for Epidermal Integrity , 2008, PLoS biology.