Albert Liu

Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf

Connector enhancer of KSR (CNK) is a multidomain protein that participates in Ras signaling in Drosophila eye development. In this report we identify the human homologue of CNK, termed CNK2A, and a truncated alternatively spliced variant, CNK2B. We characterize CNK2 phosphorylation, membrane localization, and interaction with Ras effector molecules. Our results show that MAPK signaling appears to play a role in the phosphorylation of CNK2 in vivo. CNK2 is found in both membrane and cytoplasmic fractions of the cell. In MDCK cells, full‐length CNK2 is localized to the lateral plasma membrane. Consistent with previous reports, we show CNK2 interacts with Raf. CNK2 interaction was mapped to the regulatory and kinase domains of Raf, as well as to the carboxyl‐terminal half of CNK2. CNK2 also interacts with the Ral signaling components, Ral GTPase, and the Ral‐GDS family member Rlf. CNK2 interaction was mapped to the GEF domain of Rlf. The ability of CNK2 to interact with both Ras effector proteins Raf and Rlf suggests that CNK2 may integrate signals between MAPK and Ral pathways through a complex interplay of components.—Lanigan T. M., Liu A., Huang Y. Z., Mei L., Margolis B., Guan K.‐L. Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. FASEB J. 17, 2048–2060 (2003)

High-resolution nonlinear optical spectroscopy of InGaN quantum dots in GaN nanowires

Using frequency-domain nonlinear spectroscopy methods, we find relatively broad (∼20–30u2009u2009meV) resonances from quantum confined electron–hole pairs in an ensemble of InGaN disks in GaN nanowires that persist without significant broadening up to room temperature in the nonlinear absorption spectrum. Under these growth conditions, we find that the kinetics related to the nonlinear signal are dominated by metastable traps with decay rates of microseconds at low temperatures, as evidenced in part by high-frequency-resolution scans within the broad absorption resonances. The data reveal ultranarrow population pulsation resonances with linewidths that indicate the slow decay rate of the metastable traps.

Abstract 1447: Identification of an oncogenic germline KRAS truncating mutation in hereditary cancers

Somatic strongly activating KRAS mutations play an oncogenic role across numerous human cancers, while less activating germline KRAS mutations are associated with developmental disorders. KRAS encodes two splice variant products—KRAS-4A and KRAS-4B—differing in their C-terminus through alternative fourth coding exons. Though KRAS-4A is homologous to the original transforming transcript identified in Kirsten rat sarcoma virus, its role in human cancer is less characterized compared to KRAS-4B. Here, through genetic analyses of three cohorts of patients with hereditary and/or aggressive cancers, we identified a rare KRAS-4A specific C-terminal truncating germline mutation (KRAS-4A C180X; rs373169526) in affected men of three families with hereditary prostate cancer and a patient with hereditary melanoma (minor allele frequency [MAF] of 0.0014 in these combined cancer cohorts assessed vs. 0.000056 in the ExAC population database, odds ratio 24.6 [95% confidence interval 5.1-103.5], two sided Fisher’s exact test p = 9.0E-5). The KRAS-4A C180X mutation truncates the C-terminus, removing the polybasic region and -CAAX motifs previously demonstrated to be necessary for Ras family member membrane association, MAP kinase signaling activation and transformation, suggesting a loss of function phenotype. However, in silico assessment of reported human variation demonstrates truncating germline variants only in KRAS-4A and not KRAS-4B, consistent with tolerance. Expression of KRAS-4A protein in NIH3T3 and MDCK leads to loss of exclusive membrane association and inhibits GTP loading, as expected, but paradoxically resulted in modest but significantly increased proliferation and soft agar colony growth compared to control or wildtype KRAS expressing cells. Pro-oncogenic phenotypes were not dependent on MAPK signaling, but showed sensitivity to AKT inhibition. In summary, we identified a germline truncating KRAS-4A mutation over-represented in hereditary cancers that defines a novel mechanism of KRAS activation not dependent on the C-terminal polybasic and -CAAX motifs. Citation Format: Moloy T. Goswami, Daniel H. Hovelson, Anna Johnson, Scott A. Tomlins, Lucy Wang, Kimberly Zhulke, Bhavneet Singh, Sharath Kumar Anand, Andi Cani, Albert Liu, Steven Kamberov, Yi-Mi Wu, Dan Robinson, Arul Chinnaiyan, Kathleen A. Cooney. Identification of an oncogenic germline KRAS truncating mutation in hereditary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1447. doi:10.1158/1538-7445.AM2017-1447

Exciton states in InGaN nano-disks in GaN nanowires revealed using nonlinear laser spectroscopy

Linear and coherent non-linear resonant high resolution laser spectroscopy was used to characterize In0.54Ga0.46N disks in nanowires. Nonlinear optical spectroscopy and PLE reveal narrow excitonic resonances and evidence of coupling between separate excited states.