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Kathleen Mulder

TitleProfessor
InstitutionCollege of Medicine
DepartmentBiochemistry and Molecular Biology
Address500 University Drive Hershey PA 17033
Mailbox: H171
Phone7175316789

 Overview 
 overview
PREFERRED TITLE/ROLE:

Professor of Biochemistry and Molecular Biology

SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):

Penn State Hershey Cancer Institute, Experimental Therapeutics

GRADUATE PROGRAM AFFILIATIONS:

Biomedical Sciences: Biochemistry & Genetics, Cell and Molecular Biology, Genetics, Integrative Biosciences, MD/PhD Degree Program, Pharmacology

EDUCATION:

Ph.D., SUNY at Buffalo, 1985
Postdoctoral Training, Baylor College of Medicine, 1985-1988

NARRATIVE:

km23: A novel TGFß receptor-interacting protein important in the trafficking of TGFß signaling components

km23 is a novel "motor receptor" involved in TGFß signaling (Ding and Mulder, CTR 119:315-27, 2004; Jin et al, 2007b). We have constructed the model shown below to depict the intracellular functions of km23. Upon phosphorylation of km23 by the TGFß receptors (TßRs), km23 helps to recruit endosomal TGFß signaling components to the dynein motor complex through the intermediate chain (DIC). This km23-containing motor complex facilitates the trafficking of endosomal complexes containing TGFß signaling components along the microtubules toward the nucleus. After trafficking through multiple vesicular compartments, TGFß signaling complexes can be translocated to the nucleus for transcriptional regulation of target genes, at which time they are no longer co-localized with km23. Smad2 is shown as an example of a relevant TGFß signaling component in the model below (Jin et al, JBC 282, PIP, Apr 9 2007). We are currently identifying other cargoes (ie, endosomal signaling complexes) that km23 helps transport along the microtubules. In addition, we are identifying the precise serine residues on km23 that are phosphorylated by TGFß as well as other upstream kinases involved in km23 phosphorylation.

A light chain of the motor protein dynein frequently altered in human ovarian cancer

We have cloned a novel TGFß receptor-interacting protein, termed km23 (Tang et al, MBC 13:4484-96, 2002). This protein is the mammalian homologue of the km23/LC7/robl/DYNLRB/Dnlc2 family of dynein light chains (DLCs). TGFß stimulates not only the phosphorylation of km23, but also the recruitment of km23 to the dynein intermediate chain (DIC). Kinase-active TGFß receptors are required for km23 phosphorylation and interaction with DIC (Tang et al, MBC 13:4484-96, 2002). Moreover, km23 can mediate specific TGFß responses, including activation of Jun N-terminal kinases (JNKs), phosphorylation of c-Jun, and growth inhibition. Blockade of km23-1 results in reduced Smad2-dependent TGFß signaling. Furthermore, we have identified altered forms of km23 both in TGFß-resistant human ovarian cancer cell lines and in cancer tissues from ovarian cancer patients (Ding and Mulder, CTR 119:315-27, 2004; Ding et al, CR 65:6526-33, 2005). Our data suggest that these alterations in km23 modify km23 functions in TGFß signaling and tumorigenesis. We have also shown that km23 may be a tumor suppressor for ovarian cancer. Novel functions of km23, in addition to its role in TGFß signaling, have also been identified and indicate that km23 plays an important role during mitosis. Ongoing studies are addressing the mechanisms underlying this additional critical function of km23. Further, the effects of knocking out km23 are being investigated to identify other novel functions of km23.

A novel anti-cancer target for the development of diagnostics and therapeutics

We have identified km23-1 as a novel TGFß signaling component, which is also a light chain of the motor protein dynein. We have also identified alterations of km23 in 42% of epithelial ovarian cancers from patients; these mutations do not occur in normal tissues from the same patient (Ding et al, CR 65:6526-33, 2005). In order to develop km23-based therapeutic agents, we have determined the precise three-dimensional structure of km23 (Ilangovan et al, JMB 352:338-54, 2005), and plan to compare this structure to that resulting from the mutations in km23 we have identified in the ovarian cancer patients. These studies are part of an ongoing collaboration with investigators at the University of Texas Health Sciences Center at San Antonio. We have also developed a novel screening method to detect km23 alterations in the circulating nucleic acids in the plasma/serum (CNAPS) of ovarian cancer patients. A U.S. patent was recently issued to KMM related to this method. The overall goal is to use this screening method to identify the class of patients that will respond to the km23-based therapeutics we are developing.

Biological Significance of TGFß activation of Ras/MAPKs/JNKs

We have also shown that TGFß activation of both the extracellular signal-regulated kinase (ERK) and JNK/SAPK MAPK cascades is required for the ability of TGFß to induce its own production. Further, we have identified the precise AP-1 proteins that mediate this biological response to TGFß (Yue and Mulder, JBC 275:30765-73, 2000; Yue et al, JCP 199:294-92, 2004; Liu et al, JBC 281:29479-90, 2006), and are investigating other relevant transcription factors. Understanding the precise mechanisms underlying TGFß production/secretion into the tumor microenvironment are important, since blockade of this effect in late-stage solid cancers should reverse the paracrine, tumor enhancing effects of TGFß (Liu et al, MC 45:582-93, 2006). We are currently determining which of the signaling components mediating TGFß production/secretion can be selectively targeted to block tumor progression by TGFß in vivo.

Overall Goals

The major objective of the research in the Mulder Lab is to identify alterations in TGFß signaling pathways that contribute to tumor formation or progression in ovarian, colon, and breast cancer models. Specific TGFß signaling components are being investigated as critical therapeutic targets for the restoration of negative growth control by TGFßto solid tumors. In addition, we are defining which TGFß signaling pathways lead to the growth inhibitory effects of TGFß in epithelial cells and which lead to the tumor-enhancing effects of TGFß in vivo. Selective targeting of these signaling pathways is being evaluated to determine the effects of TGFß-based therapeutics on tumor formation or progression in vivo.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Jin Q, Gao G, Mulder KM. A dynein motor attachment complex regulates TGFß/Smad3 signaling. Int J Biol Sci. 2013; 9(6):531-40.
    View in: PubMed
  2. Jin Q, Liu G, Domeier PP, Ding W, Mulder KM. Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells. PLoS One. 2013; 8(6):e66439.
    View in: PubMed
  3. Jin Q, Zhong Y, Mulder KM. Requirement for protein kinase A in the phosphorylation of the TGFß receptor-interacting protein km23-1 as a component of TGFß downstream effects. Exp Cell Res. 2013 Apr 1; 319(6):897-907.
    View in: PubMed
  4. Jin Q, Pulipati NR, Zhou W, Staub CM, Liotta LA, Mulder KM. Role of km23-1 in RhoA/actin-based cell migration. Biochem Biophys Res Commun. 2012 Nov 23; 428(3):333-8.
    View in: PubMed
  5. Jin Q, Ding W, Mulder KM. The TGFß receptor-interacting protein km23-1/DYNLRB1 plays an adaptor role in TGFß1 autoinduction via its association with Ras. J Biol Chem. 2012 Jul 27; 287(31):26453-63.
    View in: PubMed
  6. Jin Q, Gao G, Mulder KM. Requirement of a dynein light chain in transforming growth factor ß signaling in zebrafish ovarian follicle cells. Mol Cell Endocrinol. 2012 Jan 2; 348(1):233-40.
    View in: PubMed
  7. Pulipati NR, Jin Q, Liu X, Sun B, Pandey MK, Huber JP, Ding W, Mulder KM. Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase. Int J Cancer. 2011 Aug 1; 129(3):553-64.
    View in: PubMed
  8. Pandey MK, Liu G, Cooper TK, Mulder KM. Knockdown of c-Fos suppresses the growth of human colon carcinoma cells in athymic mice. Int J Cancer. 2012 Jan 1; 130(1):213-22.
    View in: PubMed
  9. Jin Q, Gao G, Mulder KM. Requirement of a dynein light chain in TGFbeta/Smad3 signaling. J Cell Physiol. 2009 Dec; 221(3):707-15.
    View in: PubMed
  10. Jin Q, Ding W, Mulder KM. Requirement for the dynein light chain km23-1 in a Smad2-dependent transforming growth factor-beta signaling pathway. J Biol Chem. 2007 Jun 29; 282(26):19122-32.
    View in: PubMed
  11. Liu G, Ding W, Neiman J, Mulder KM. Requirement of Smad3 and CREB-1 in mediating transforming growth factor-beta (TGF beta) induction of TGF beta 3 secretion. J Biol Chem. 2006 Oct 6; 281(40):29479-90.
    View in: PubMed
  12. Liu G, Ding W, Liu X, Mulder KM. c-Fos is required for TGFbeta1 production and the associated paracrine migratory effects of human colon carcinoma cells. Mol Carcinog. 2006 Aug; 45(8):582-93.
    View in: PubMed
  13. Ilangovan U, Ding W, Zhong Y, Wilson CL, Groppe JC, Trbovich JT, Zúñiga J, Demeler B, Tang Q, Gao G, Mulder KM, Hinck AP. Structure and dynamics of the homodimeric dynein light chain km23. J Mol Biol. 2005 Sep 16; 352(2):338-54.
    View in: PubMed
  14. Ding W, Tang Q, Espina V, Liotta LA, Mauger DT, Mulder KM. A transforming growth factor-beta receptor-interacting protein frequently mutated in human ovarian cancer. Cancer Res. 2005 Aug 1; 65(15):6526-33.
    View in: PubMed
  15. Jin Q, Ding W, Staub CM, Gao G, Tang Q, Mulder KM. Requirement of km23 for TGFbeta-mediated growth inhibition and induction of fibronectin expression. Cell Signal. 2005 Nov; 17(11):1363-72.
    View in: PubMed
  16. Yue J, Sun B, Liu G, Mulder KM. Requirement of TGF-beta receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-beta up-regulation of the urokinase-type plasminogen activator receptor. J Cell Physiol. 2004 May; 199(2):284-92.
    View in: PubMed
  17. Ding W, Mulder KM. km23: a novel TGFbeta signaling target altered in ovarian cancer. Cancer Treat Res. 2004; 119:315-27.
    View in: PubMed
  18. Tang Q, Staub CM, Gao G, Jin Q, Wang Z, Ding W, Aurigemma RE, Mulder KM. A novel transforming growth factor-beta receptor-interacting protein that is also a light chain of the motor protein dynein. Mol Biol Cell. 2002 Dec; 13(12):4484-96.
    View in: PubMed
  19. Yue J, Mulder KM. Transforming growth factor-beta signal transduction in epithelial cells. Pharmacol Ther. 2001 Jul; 91(1):1-34.
    View in: PubMed
  20. Yue J, Mulder KM. Requirement of Ras/MAPK pathway activation by transforming growth factor beta for transforming growth factor beta 1 production in a smad-dependent pathway J Biol Chem. 2000 Nov 10; 275(45):35656.
    View in: PubMed
  21. Yue J, Mulder KM. Requirement of Ras/MAPK pathway activation by transforming growth factor beta for transforming growth factor beta 1 production in a Smad-dependent pathway. J Biol Chem. 2000 Oct 6; 275(40):30765-73.
    View in: PubMed
  22. Mulder KM. Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev. 2000 Mar-Jun; 11(1-2):23-35.
    View in: PubMed
  23. Yue J, Mulder KM. Activation of the mitogen-activated protein kinase pathway by transforming growth factor-beta. Methods Mol Biol. 2000; 142:125-31.
    View in: PubMed
  24. Yue J, Frey RS, Mulder KM. Cross-talk between the Smad1 and Ras/MEK signaling pathways for TGFbeta. Oncogene. 1999 Mar 18; 18(11):2033-7.
    View in: PubMed
  25. Yue J, Hartsough MT, Frey RS, Frielle T, Mulder KM. Cloning and expression of a rat Smad1: regulation by TGFbeta and modulation by the Ras/MEK pathway. J Cell Physiol. 1999 Mar; 178(3):387-96.
    View in: PubMed
  26. Liu X, Yue J, Frey RS, Zhu Q, Mulder KM. Transforming growth factor beta signaling through Smad1 in human breast cancer cells. Cancer Res. 1998 Oct 15; 58(20):4752-7.
    View in: PubMed
  27. Yue J, Buard A, Mulder KM. Blockade of TGFbeta3 up-regulation of p27Kip1 and p21Cip1 by expression of RasN17 in epithelial cells. Oncogene. 1998 Jul 9; 17(1):47-55.
    View in: PubMed
  28. Frey RS, Mulder KM. TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. Cancer Lett. 1997 Jul 15; 117(1):41-50.
    View in: PubMed
  29. Frey RS, Mulder KM. Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells. Cancer Res. 1997 Feb 15; 57(4):628-33.
    View in: PubMed
  30. Hartsough MT, Mulder KM. Transforming growth factor-beta signaling in epithelial cells. Pharmacol Ther. 1997; 75(1):21-41.
    View in: PubMed
  31. Hartsough MT, Frey RS, Zipfel PA, Buard A, Cook SJ, McCormick F, Mulder KM. Altered transforming growth factor signaling in epithelial cells when ras activation is blocked. J Biol Chem. 1996 Sep 13; 271(37):22368-75.
    View in: PubMed
  32. Buard A, Zipfel PA, Frey RS, Mulder KM. Maintenance of growth factor signaling through Ras in human colon carcinoma cells containing K-ras mutations. Int J Cancer. 1996 Aug 7; 67(4):539-46.
    View in: PubMed
  33. Zhou GH, Sechrist GL, Brattain MG, Mulder KM. Clonal heterogeneity of the sensitivity of human colon carcinoma cell lines to TGE beta isoforms. J Cell Physiol. 1995 Dec; 165(3):512-20.
    View in: PubMed
  34. Zhou GH, Sechrist GL, Periyasamy S, Brattain MG, Mulder KM. Transforming growth factor beta isoform-specific differences in interactions with type I and II transforming growth factor beta receptors. Cancer Res. 1995 May 15; 55(10):2056-62.
    View in: PubMed
  35. Hartsough MT, Mulder KM. Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem. 1995 Mar 31; 270(13):7117-24.
    View in: PubMed
  36. Zipfel PA, Ziober BL, Morris SL, Mulder KM. Up-regulation of transforming growth factor alpha expression by transforming growth factor beta 1, epidermal growth factor, and N,N-dimethylformamide in human colon carcinoma cells. Cell Growth Differ. 1993 Aug; 4(8):637-45.
    View in: PubMed
  37. Mulder KM, Segarini PR, Morris SL, Ziman JM, Choi HG. Role of receptor complexes in resistance or sensitivity to growth inhibition by TGF beta in intestinal epithelial cell clones. J Cell Physiol. 1993 Jan; 154(1):162-74.
    View in: PubMed
  38. Mulder KM, Morris SL. Activation of p21ras by transforming growth factor beta in epithelial cells. J Biol Chem. 1992 Mar 15; 267(8):5029-31.
    View in: PubMed
  39. Wu SP, Theodorescu D, Kerbel RS, Willson JK, Mulder KM, Humphrey LE, Brattain MG. TGF-beta 1 is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector. J Cell Biol. 1992 Jan; 116(1):187-96.
    View in: PubMed
  40. Mulder KM. Differential regulation of c-myc and transforming growth factor-alpha messenger RNA expression in poorly differentiated and well-differentiated colon carcinoma cells during the establishment of a quiescent state. Cancer Res. 1991 May 1; 51(9):2256-62.
    View in: PubMed
  41. Mulder KM, Humphrey LE, Choi HG, Childress-Fields KE, Brattain MG. Evidence for c-myc in the signaling pathway for TGF-beta in well-differentiated human colon carcinoma cells. J Cell Physiol. 1990 Dec; 145(3):501-7.
    View in: PubMed
  42. Mulder KM, Zhong Q, Choi HG, Humphrey LE, Brattain MG. Inhibitory effects of transforming growth factor beta 1 on mitogenic response, transforming growth factor alpha, and c-myc in quiescent, well-differentiated colon carcinoma cells. Cancer Res. 1990 Dec 1; 50(23):7581-6.
    View in: PubMed
  43. Mulder KM, Childress-Fields KE. Characterization of a serum-free culture system comparing growth factor requirements of transformed and untransformed cells. Exp Cell Res. 1990 Jun; 188(2):254-61.
    View in: PubMed
  44. Mulder KM, Brattain MG. Effects of growth stimulatory factors on mitogenicity and c-myc expression in poorly differentiated and well differentiated human colon carcinoma cells. Mol Endocrinol. 1989 Aug; 3(8):1215-22.
    View in: PubMed
  45. Mulder KM, Levine AE, Hinshaw XH. Up-regulation of c-myc in a transformed cell line approaching stationary phase growth in culture. Cancer Res. 1989 May 1; 49(9):2320-6.
    View in: PubMed
  46. Hoosein NM, McKnight MK, Levine AE, Mulder KM, Childress KE, Brattain DE, Brattain MG. Differential sensitivity of subclasses of human colon carcinoma cell lines to the growth inhibitory effects of transforming growth factor-beta 1. Exp Cell Res. 1989 Apr; 181(2):442-53.
    View in: PubMed
  47. Mulder KM, Brattain MG. Continuous maintenance of transformed fibroblasts under reduced serum conditions: utility as a model system for investigating growth factor-specific effects in nonquiescent cells. J Cell Physiol. 1989 Mar; 138(3):450-8.
    View in: PubMed
  48. Mulder KM, Ramey MK, Hoosein NM, Levine AE, Hinshaw XH, Brattain DE, Brattain MG. Characterization of transforming growth factor-beta-resistant subclones isolated from a transforming growth factor-beta-sensitive human colon carcinoma cell line. Cancer Res. 1988 Dec 15; 48(24 Pt 1):7120-5.
    View in: PubMed
  49. Mulder KM, Brattain MG. Alterations in c-myc expression in relation to maturational status of human colon carcinoma cells. Int J Cancer. 1988 Jul 15; 42(1):64-70.
    View in: PubMed
  50. Mulder KM, Levine AE, Hernandez X, McKnight MK, Brattain DE, Brattain MG. Modulation of c-myc by transforming growth factor-beta in human colon carcinoma cells. Biochem Biophys Res Commun. 1988 Jan 29; 150(2):711-6.
    View in: PubMed
  51. Mulder KM, Kostyniak PJ. Effect of L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid on urinary excretion of methylmercury in the mouse. J Pharmacol Exp Ther. 1985 Jul; 234(1):156-60.
    View in: PubMed
  52. Mulder KM, Kostyniak PJ. Involvement of glutathione in the enhanced renal excretion of methyl mercury in CFW Swiss mice. Toxicol Appl Pharmacol. 1985 May; 78(3):451-7.
    View in: PubMed
  53. Mulder KM, Kostyniak PJ. Stabilization of glutathione in urine and plasma: relevance to urinary metal excretion studies. J Anal Toxicol. 1985 Jan-Feb; 9(1):31-5.
    View in: PubMed
  54. Roth JA, Eddy BJ, Pearce LB, Mulder KM. Phenylhydrazine: selective inhibition of human brain type B monoamine oxidase. Biochem Pharmacol. 1981 May 1; 30(9):945-50.
    View in: PubMed
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