The pathophysiological significance of this role in intestinal barrier protection is underscored by the impact of GUCY2C signaling on colitis and systemic genotoxicity and tumorigenesis. In turn, these considerations highlight the translational opportunities for GUCY2C ligands in the prevention and treatment of inflammatory bowel disease and extra-intestinal malignancies. This therapeutic potential is underscored by the recent advancement of the oral GUCY2C ligand linaclotide for FDA approval for the treatment of constipation-type irritable bowel syndrome. In mammals, there are four Par-1 homologs that comprise the MARK family. This family consists of four closely related proteins that have been shown to play a role in cell polarity, microtubule stability, protein stability, and cell cycle control. Although similar in structure, the MARK proteins have different subcellular localizations. Phosphorylation of many MARK targets generates a 14-3-3 binding site. 14-3-3 regulates the subcellular localization of many proteins. Two mark2-/- mouse lines have been independently generated that implicate MARK2 in the regulation of immune homeostasis, fertility, learning, memory, growth and metabolism. C-TAK1 has been implicated in pancreatic, liver, and colorectal cancers, hippocampal function, and metabolism. In C. elegans Par-1 plays Corosolic-acid a negative role in vulva induction and may function by negatively regulating the scaffolding protein KSR1. In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392. Phosphorylation of this site sequesters KSR1 in the cytoplasm. KSR1 is a molecular scaffold of the Raf/MEK/ERK MAP kinase pathway. KSR1 enhances Raf-1 activity in a kinase-independent manner. Proteomic analys reveal that MARK2 interacts with KSR1 and we have shown that MARK2, similar to C-TAK1, is able to phosphorylate KSR1 in vitro on S392. This phosphorylation site has been shown previously to be a negative regulatory site of KSR1. This result predicts that MARK2 negatively regulates KSR1 as an ERK scaffold. However, it is also possible that KSR1 serves as a scaffold for MARK2 similar to the interaction of KSR1 with ERK. As the MARK family contains multiple members, it is possible that other members of the MARK family are able to compensate for the loss of MARK2. However,Acetylcorynoline though the family has a high degree of homology, the subcellular localization varies. MARK1, MARK2, and C-TAK1 are all basolateral, but C-TAK1 is also found on the apical surface. MARK4 does not display asymmetric localization, but interacts with filamentous structures. The family members are also differentially regulated. MARK2 localizes to the cytoplasm upon overexpression of PKCf. However, MARK1 and C-TAK1 do not alter their localization when PKCf is overexpressed. This observation suggests that other members of the MARK family may not fully compensate for the loss of MARK2. These data raise the possibility that different stimuli could selectively recruit related members of a kinase family to impair KSR1 function through phosphorylation of a common site. In this model, KSR1 would integrate different signals to the same effect. These mechanisms may allow KSR1 to respond to signals in different cell types or in multiple subcellular compartments. The potential of KSR1 to receive input at the same site from multiple kinases may also affect the intensity and/or duration of KSR1mediated signaling by increasing the stoichiometry of KSR1 phosphorylation on Ser392. Observational studies supporting this hypothesis include a report that infection with the nematode Strongyloides stercoralis is associated with protection against autoimmune liver disease, and another showing that unspecified helminth infections with peripheral eosinophilia are associated with reduced autoantigen-specific responses and disease progression in multiple sclerosis.