This is supported by the findings of Haithcock et al., who showed that loss of C. elegans lamin reduced lifespan and caused nuclear changes associated with aging. With minimal extracellular domains, DAP12 and FcRc have no known ability to bind ligands. In the present study, we focused our investigation on the role of the KCNE1 C-terminus on regulation and rate-adaptation of IKs. Our data show that deactivation kinetics—a parameter that has thus far been given little attention is significantly affected by mutations in the C-terminus. We also provide evidence that the Cterminus truncation or mutation also renders the channel incapable of adapting IKs current accumulation in response to increases in pulse rate as does the channel formed by wild-type KCNE1. Thus, interactions between the KCNE1 C-terminus and KCNQ1 may play a critical physiological role in rate-related adaptation of action potential duration, the dysregulation of which could contribute to LQT1 and LQT5 phenotypes. Therefore, they are insufficient to sense the local microenvironment alone. The DAP12 and FcRc signaling adapters associate with innate immune transmembrane receptors that have ligand recognition domains. Innate immune receptors are genetically encoded to sense environmental changes and provide front line defense against infection. Certain activating innate immune receptors, such as Dectin-1 , use intrinsic ITAMs to transduce activating signals ; however, there is also a class of innate immune receptors that lack signaling motifs in their intracellular domains. To uncover other potential gain-of-function somatic mutations that could have biological and clinical relevance in lung cancer, we performed mutational profiling of a large cohort of lung tumors, mostly adenocarcinomas. Because multiple genes that encode proteins in the EGFR signaling pathway have been found to be mutated in lung CUDC-907 adenocarcinomas, we specifically sought to identify potential gain-of-function mutations in gene families in this pathway. As suggested by these independent results, CQ may actually act on multiple molecular targets in parallel, which could explain its extraordinary effectiveness over a long period of time. In our study, most proteins showing increases in expression are localized to the nucleus or interact with chromosomes. The overt phenotype associated with Cobra1 KO/knockdown is reminiscent of those associated with disruption of the master regulator genes. However, unlike the master regulators, Cobra1 expression is not limited to pluripotent stem cells, suggesting that its function is necessary but not sufficient for pluripotency. Within the context of ESCs, an important function of Cobra1 may be to help maintain developmental genes in a repressed yet poised transcriptional state. Consistent with this notion, Cobra1 depletion leads to elevated transcription of multiple developmental genes in ESCs without affecting the levels of Oct4, Nanog, orSox2.