SCRIB

SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold is_associated_with::protein which in humans is encoded by the SCRIB is_associated_with::gene. It was originally isolated in is_associated_with::Drosophila melanogaster in a pathway (also known as the Scribble complex) with is_associated_with::DLGAP5 (Discs large) and is_associated_with::LLGL1 (Lethal giant larvae) as a tumor suppressor. In humans, SCRIB is found as a membrane protein and is involved in is_associated_with::cell migration, is_associated_with::cell polarity, and is_associated_with::cell proliferation in is_associated_with::epithelial cells. There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.

Function
In is_associated_with::Drosophila melanogaster, SCRIB is involved in synaptic function, neuroblast differentiation, and epithelial polarization. Mechanistically, the human is_associated_with::homolog is a scaffold protein linked to is_associated_with::cellular differentiation centered on the regulation of epithelial as well as neuronal morphogenesis. Deficiency in SCRIB impairs many aspects of cell polarity and cell movement. SCRIB is also likely involved in establishing apical-basal polarity as well as progression from the is_associated_with::G1 phase to is_associated_with::S phase in the is_associated_with::cell cycle as a result of its relationship with is_associated_with::cell proliferation and is_associated_with::exocytosis.

The transcribed protein products of the SCRIB gene along with is_associated_with::DLGAP5 (Discs large) and is_associated_with::LLGL1 (Lethal giant larvae) are components of the Scribble complex that is localized in the basolateral membrane. The Scribble complex plays a role in determining is_associated_with::cell polarity and is_associated_with::cell proliferation in is_associated_with::epithelial cells. The precise mechanism by which these proteins function together is currently unknown, but they have been implicated in several signaling pathways, vesicle trafficking, and in the is_associated_with::myosin II-actin cytoskeleton. The Scribble complex has been shown to promote basolateral membrane identity by antagonizing both the Par complex and the Crumbs complex, which promote apical membrane identity. These genes have also been identified as tumor suppressors in Drosophila melanogaster. Since these genes are highly conserved in humans, there is evidence that they play a role in cancer progression.

Structure
The human homolog is a LAP protein, it contains 16 is_associated_with::leucine-rich repeats and four is_associated_with::PDZ domains. SCRIB belongs to a protein complex containing betaPIX, an exchange factor for Rac/Cdc42, and is_associated_with::GIT1, a GTPase activating protein for is_associated_with::ARF6 implicated in receptor recycling and exocytosis.

Subcellular and tissue distribution
SCRIB is found in the cell membrane most often as a is_associated_with::peripheral membrane protein. The Scribble complex is localized at the basolateral membrane. SCRIB is also found in cellular junctions such as is_associated_with::adherens junctions and is_associated_with::tight junctions. Specifically, it is located in the is_associated_with::kidney, is_associated_with::skeletal muscles, is_associated_with::liver, is_associated_with::lung, is_associated_with::breast, is_associated_with::intestine, is_associated_with::placenta and is_associated_with::epithelial cells.

Clinical significance
The is_associated_with::PDZ domain of SCRIB binds directly to the is_associated_with::human papillomavirus E6 protein. SCRIB is targeted for is_associated_with::ubiquitination by a complex of E6 and is_associated_with::UBE3A and E6 induces degradation of SCRIB.

Role as a tumor suppressor
As mentioned above, SCRIB has been identified as a tumor suppressor along with is_associated_with::DLGAP5 (Discs large) and is_associated_with::LLGL1 (Lethal giant larvae). Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous is_associated_with::oncogenes. For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes is_associated_with::neoplastic growth by disrupting is_associated_with::morphogenesis and inhibiting is_associated_with::cell death through an association with is_associated_with::Myc. In human cells expressing is_associated_with::oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the is_associated_with::extracellular matrix by various cell types. This is believed to be a direct result of regulation of the is_associated_with::MAP Kinase pathway by SCRIB.

Role in epithelial mesenchymal transition (EMT)
Due to its role in is_associated_with::cell polarity and is_associated_with::cell motility, SCRIB has also been implicated in is_associated_with::epithelial mesenchymal transition (EMT), which is linked to tumor is_associated_with::metastasis and proliferation in many is_associated_with::cancers. EMT is implicated in cancer progression by allowing static is_associated_with::epithelial cells to become migratory and allowing these cells to adapt to as well as colonize new environments. In cancerous epithelial tissues, SCRIB is found primarily in the cytosol as opposed to its usual location in the membrane, thus further implicating a role in tumor progression and EMT for SCRIB.

Knockdown mutants have resulted in the loss of adhesion between Madin-Darby canine kidney epithelial cells. This loss of adhesion was correlated with an acquired is_associated_with::mesenchymal appearance, an increase in motility, and loss of directionality. These effects were a direct result of the interruption of is_associated_with::E-cadherin-mediated cellular adhesion. A decrease in cell migration and an overall decrease in cell motility markers as well as is_associated_with::epithelial mesenchymal transition mediators was also observed in small lung adenocarcinoma cells that were depleted of SCRIB.