Transition between proliferation and differentiation for lens epithelial cells is regulated by Src family kinases.
As in many cell types, lens cells must withdraw from the cell cycle before they initiate their differentiation. The involvement of Src family kinases (SFKs) in this key initiating event in cell differentiation was examined in lens epithelial cell cultures. SFK activity was suppressed with the specific inhibitor PP1. This induced expression of the cyclin-dependent kinase (CDK) inhibitors p27 and p57 and suppressed lens epithelial cell proliferation. Therefore, inhibition of SFK activity created conditions permissive for undifferentiated lens epithelial cells to withdraw from the cell cycle. Growth of the lens epithelial cell cultures in the presence of PP1 induced expression of filensin and CP49, lens differentiation-specific intermediate filament proteins, providing evidence that suppression of SFK activity also promoted the initiation of lens cell differentiation. The mechanism by which PP1 signaled cell cycle withdrawal and commitment to differentiation was shown to involve induction of N-cadherin cell-cell junction assembly and reorganization of the actin cytoskeleton from stress fibers to cortical filaments. This result was supported by the compaction of the epithelial monolayer in response to PP1, a morphogenetic change that we have previously shown to be dependent on N-cadherin function and a hallmark of the commencement of the lens differentiation program in culture. The results presented in this study suggest that the decision of lens epithelial cells to withdraw from the cell cycle and initiate differentiation requires inhibition of SFKs and the formation of N-cadherin cell-cell junctions.
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Janice L
JL
Walker
Liping
L
Zhang
A Sue
AS
Menko
D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005136:Eye Proteins / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000166:cytology* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D011784:Quail / Q000196:embryology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000199:Actins; D015820:Cadherins; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D039503:Integrin alpha6; D007381:Intermediate Filament Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; C079098:filensin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases