My lab in interested in signal transduction by
tyrosine kinases, with a particular emphasis upon members of the Src family of
tyrosine kinases. We primarily work on
the receptor for prolactin. Prolactin
stimulates the proliferation and differentiation of mammary epithelial cells,
and perhaps is best known for stimulating the transcription of milk protein
genes. Prolactin also maintains the
viability of mammary epithelial cells during lactation by suppressing programmed
cell death. We have demonstrated that
Src-like kinases are required for activation of mitogenic and anti-apoptotic
signaling pathways downstream of both of these receptors. Specifically, Src-like kinases appear to
regulate the activation of phosphatidylinositol 3-kinase and the subsequent
activation of the anti-apoptotic protein kinase Akt. We are currently determining the mechanism by which Src-like
kinases are activated and what intermediates regulate Akt activation. This includes an analysis of mammary gland
development in mice that lack expression of specific Src family kinases.
Our interest in Akt has also led us to examine the
role of Akt in mammary gland development and tumorigenesis. We have generated transgenic mice that
express a constitutively activated mutant of Akt in mammary gland and have
demonstrated that Akt significantly delays mammary gland involution, an
apoptotic process in which perhaps 80% of mammary epithelial cells die. In addition, it appears that a preneoplatic
state is established in these mice which predisposes them to mammary
cancer. We are currently characterizing
these mice to identify potential substrates for Akt, as well as genes whose
transcription maybe regulated by Akt. Future
studies will address what oncogenes cooperate with Akt in generating mammary
tumors, and whether Akt is activated in human breast cancer.
Selected Publications
Lee RCH, Walters JA, Reyland ME and Anderson
SM (1999) " Constitutive activation of the prolactin receptor results in the induction of growth-factor-independent proliferation and
constitutive activation of signaling
molecules," J Biol Chem 274:10024-10034.
Hunter S, Burton EA, Wu SC and Anderson, SM (1999)
"Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphstidylinositol
3-kinase," J Biol Chem 274:2097-2106.
Anderson SM, Reyland ME, Hunter S, Diesher LM,
Barzen KA, and Quissel DO (1999) Etoposide-induced
activation of c-jun N-terminal kinase (JNK)
correlates with drug-induced apoptosis in salivary
gland acinar cells. Cell Death and
Differentiation 6, 454-462.
Reyland ME, Anderson SM, Matassa
AA, Barzen KA, and Quissel DO (1999) Protein kinase
C delta is essential for etoposide-induced apoptosis
in salivary gland acinar cells. J. Biol.
Chem. 274, 19115-19123.
Gibson S, Tu S, Oyer R, Anderson
SM, and Johnson GL (1999) Epidermal growth factor
protects epithelial cells against fas induced
apoptosis: Requirement for Akt
activation. J. Biol. Chem. 274,
17612-17618.
Gibson SB, Oyer R, Spalding AC,
Anderson SM, and Johnson GL (2000) Increased
expression of death receptors 4 and 5 synergizes the
apoptosis response to combined treatment with
etoposide and TRAIL. Mol. Cell. Biol. 20,
205-212.
Richert MM, Schwertfeger KL, Ryder
JW, and Anderson SM (2000) An atlas of mouse mammary
gland development. J. Mammary Gland Dev.
Neoplasia, 5:227-241.
Matassa A, Barzen KA, Anderson SM,
Quissell DO, and Reyland ME (2000) Activation
of PKC is sufficient to induce an apoptotic program
in salivary gland acinar cells. Cell Death
and Differentiation, 7:1200-1209.
Schwertfeger KL, Hunter S, Heasley
LE, Leon RP, DeGregori J, and Anderson SM (2001) Prolactin stimulates activation of c-jun
N-terminal kinase (JNK). Mol. Endocrinol.,
15:867-881.
Schwertfeger KL, Richert MM, and
Anderson, SM (2001) Mammary gland involution is
delayed by activated Akt in transgenic mice. Mol.
Endocrinol. 15, 867-881.
Boonyaratanakornkit
V, Scott MP, Ribon V, Sherman L, Anderson SM, Maller
JL, Miller WT, and Edwards, DP (2001) Progesterone
receptor contains a proline-rich motif that directly
interacts with SH3 domains and activates c-Src
family tyrosine kinases. Mol. Cell 8:269-280.
Kassenbrock CK, Hunter S, Garl PM,
Johnson GL, and Anderson SM, 2002. "Inhibition of Src family kinases blocks EGF-induced
activation of Akt, phosphorylation of Cbl, and ubiquitination of the EGF
receptor." Journal of Biological Chemistry 277: 24967-24975.
Limesand, KH, Barzen KA, Quissell DO, and
Anderson SM (2003) Synergistic suppression of apoptosis in salivary acinar
cells by IGF1 and EGF: Role of Akt. Cell Death and Differentation, in
press.
Sun W, Wei X, Kesavan K, Garrigton TP, Fan R,
Mei J, Anderson SM, Gelfand EW, and Johnson GL (2003) MEKK2 and the adapter
protein Lad regulate ERK5 activation by EGF via Src. Molecular and Cellular
Biology, in press.
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