Research Interests

Regulation of the cell function via trafficking of signaling molecules

The important question in my research is how cellular function is dynamically regulated by local activation of cell signaling. To induce the signaling locally, the signaling molecules need to be accumulated at the particular area of the cells. The accumulation of the molecules is mediated by the intracellular trafficking by the molecular motors; kinesins, dyneins, and myosins. Among them, we are particularly interested in the kinesin family protein, KIF13B, as it transports important signaling molecules, such as VEGFR2.

Trafficking of VEGFR2 by KIF13B is critical for angiogenesis, the formation of the new blood vessels from pre-existing vessels. Angiogenesis is a hallmark of cancer and blinding eye diseases such as wet age-related macular degeneration (wet AMD) and diabetic retinopathy. Pathogenic angiogenesis is induced by an excess amount of vascular endothelial growth factor (VEGF) in the diseased tissue. To response to VEGF, VEGFR2 needs to be exposed at the cell surface of endothelial cells. We found that the trafficking of VEGFR2 to the cell surface is mediated by a kinesin motor KIF13B. Based on the finding, we developed a small peptide inhibitor disrupting the interaction between VEGFR2 and KIF13B, thus inhibiting VEGFR2 trafficking. This peptide inhibitor successfully inhibited pathological angiogenesis in wet AMD and cancer.

Our projects focus on understanding the role of intracellular trafficking in the cell function, particularly dynamic cell sprouting in angiogenesis. Using live cell imaging of VEGFR2 in sprouting angiogenesis, we will tackle the interesting questions; how the trafficking is regulated, how the direction of the trafficking is decided, and what happens if the trafficking is activated or blocked. Moreover, using the mouse models of endothelial-specific KIF13B knockout and the aforementioned pharmacological inhibitor in disease models, such as cancer models, wet AMD models, and diabetic retinopathy models, we will address the role of the trafficking in progression of diseases, and whether we can develop the strategy to regulate the trafficking to inhibit pathological angiogenesis in these diseases.

Cho, H.D, Nhàn, N.T.T., Zhou, C., Tu, K., Nguyen, T, Sarich, N.A., & Yamada, K.H. (2023) KIF13B mediates VEGFR2 recycling to modulate vascular permeability. Cellular and Molecular Life Sciences. Mar 16;80(4):91 PMID: 36928770 DOI: 10.1007/s00018-023-04752-5

Waters, S.B., Dominguez, J.R., Cho, H-D., Sarich, N.A., Malik, A.B., Yamada, K.H. (2022), KIF13B-mediated VEGFR2 trafficking is essential for vascular leakage and metastasis in vivo.  Life Sci Alliance Oct 20;5(1):e202101170 PMCID: PMC8548263  DOI: 10.26508/lsa.202101170

Waters, S. B., Zhou, C., Nguyen, T., Zelkha, R., Lee, H., Kazlauskas, A., Rosenblatt, M. I., Malik, A. B., and Yamada, K. H., (2021), VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration., Investigative Ophthalmology & Visual Science February 1;62(2):5 PMCID: PMC7862734 DOI: 10.1167/iovs.0.0.31012.

Yamada, K. H., Kang, H., Malik, A. B., (2017) Antiangiogenic Therapeutic Potential of Peptides Derived from the Molecular Motor KIF13B that Transports VEGFR2 to Plasmalemma in Endothelial Cells. Am J Pathol. Jan;187(1):214-224. PMCID: PMC5225310

Yamada, K. H., Nakajima, Y., Geyer, M., Wary, K. K., Ushio-Fukai, M., Komarova, Y., and Malik, A. B., (2014) KIF13B Regulates Angiogenesis through Golgi-Plasma Membrane Trafficking of VEGFR2. J. Cell Sci October 15;127 (Pt 20):4518-30. PMCID: PMC4197089

Yamada, K.H., Kozlowski, D.A., Seidl, S.E., Lance, S., Wieschhaus, A.J., Sundivakkam, P., Tiruppathi, C., Chishti, I., Herman, I.M., Kuchay, S.M., Chishti, A.H. (2012) Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress. J. Biol. Chem. 287 (16):13182-93 PMCID: PMC3339949

Tong, Y., Tempel, W., Wang, H., Yamada, K., Shen, L., Senisterra, G. A., MacKenzie, F., Chishti, A. H., Park, H. W., (2010) Phosphorylation-independent binding specificity of the KIF13-FHA domain mediates phosphoinositide transport. Proc. Nat. Acad. Sci. 23;107(47):20346-51. PMCID: PMC2996657

Yamada, K. H., Hanada, T., and Chishti, A. H., (2007) The effector domain of human Dlg tumor suppressor acts as a switch that relieves autoinhibition of kinesin-3 motor GAKIN/KIF13B. Biochemistry. September 4;46(35):10039-45. PMCID: PMC2525504

Horiguchi, K., Hanada, T., Fukui, Y., and Chishti, A. H., (2006) Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity. J Cell Biol., 174:425-36. PMCID: PMC2064238

Tanaka, K., Horiguchi, K., Yoshida, T., Takeda, M., Fujisawa, H., Takeuchi, K., Umeda, M., Kato, S., Ihara, S., Nagata, S., and Fukui, Y., (1999) Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus. J Biol Chem. 274:3919-22. PMID: 9933577 DOI: 10.1074/jbc.274.7.3919

A member of the NIH ZNS1 SRB-Q (7), (9), and (11), NIH Blueprint Neurotherapeutics Network (BPN) Review Panel

Ad hoc reviewer for the NIH study section PED2

Ad hoc reviewer for the NIH study section IVPP

Ad hoc reviewer for American Cancer Society (ACS) Experimental Therapeutic Peer Review

B.Sc., The University of Tokyo, Tokyo, Japan; Biology (1999).
M.S., The University of Tokyo, Tokyo, Japan; Biochemistry (2001).
PhD, The University of Tokyo, Tokyo, Japan; Biochemistry (2007).
Postdoc, University of Illinois at Chicago; Cell Biology (2009).

AACR, ASCB, NAVBO, ARVO, ISER, AHA

Yamada, K. H. (2024) KIF13B mediates VEGFR2 recycling to modulate vascular permeability in nAMD.  IOVS 2024 October

Yamada, K. H. (2021) VEGFR2 trafficking by KIF13B is a novel therapeutic target for wet AMD.  ARVO 2021 May

Yamada, K. H., and Malik A. B., (2019) Regulation of Angiogenesis via Endoplasmic Reticular to Plasmalemmal via VEGFR2 Trafficking.  Gordon Conference 2019 Vascular Cell Fate, Metabolism and Targeting, Ventura, CA, January

Yamada, K. H., Waters, S., Rosenblatt, M. I., Kazlauskas, A., and Malik A. B., (2018) Selectively targeting VEGFR2 trafficking in endothelial cells prevents wet AMD.  International Society for Eye Research 2018, Belfast Northern Ireland, UK, September

We are studying the mechanism of how vascular cells respond in diseases.  We have 3 projects in our lab;

1. The mechanisms of subretinal fibrosis development in neovascular age-related macular degeneration (AMD)
2. The mechanisms of how uveal melanoma escapes from the eyes to metastasize to the liver.
3. The mechanisms of how breast cancer invades the brain through the tightest barrier of the blood brain barrier (BBB).

Neovascular AMD

Neovascular AMD (nAMD) is a blinding disease for old patients. Excessive expression of vascular endothelial growth factor (VEGF) is a hallmark of nAMD, inducing massive angiogenesis and vascular leakiness. Angiogenesis is a form of grouped cell migration forming new vessels from pre-existing blood vessels. Then, how do the cells know which direction to migrate? The cells sense the gradient of the growth factors and accumulate the receptors of the growth factors at the area facing the growth factors. Such accumulation of molecules is mediated by molecular motors in the cells, such as kinesins, dynein, and myosins. We searched for molecular motors responsible for the trafficking of the receptor for VEGF, VEGFR2, and found a kinesin family motor, KIF13B. We developed a strategy inhibiting KIF13B-mediated VEGFR2 trafficking, thus limiting the amount of VEGFR2 on the cell surface by a peptide named KAI, a kinesin-derived angiogenesis inhibitor.  KAI showed efficacy in inhibiting angiogenesis and vascular leakage in animal models of nAMD.

Current therapy of neutralizing excess amounts of VEGF is highly effective in inhibiting vascular leakage and neovascularization; however, it is ineffective in preventing subretinal fibrosis, which is the worst prognosis in terms of visual acuity after anti-VEGF treatments.  We are studying the mechanisms of how subretinal fibrosis is developed under anti-VEGF treatments.

Uveal melanoma escaping from the eye

Uveal melanoma (UM) is a common ocular cancer with a high rate of metastasis in the liver. Metastatic UM is known to be highly vascularized with excess expression of VEGF and high activation of its receptor VEGFR2. Using the aforementioned strategy limiting the amount of VEGFR2 at the cell surface, we study whether VEGF is a reliable target to inhibit UM escaping from the eyes.

We further study how UM cells affect endothelial cells (ECs) to facilitate UM adhesion to ECs and UM cell transendothelial migration.

Breast cancer brain metastasis (BCBM)

Several cancer types, including breast cancer, tend to metastasize into the brain. Brain metastases are difficult to treat due to the challenge of drug delivery through the blood-brain barrier (BBB). The BBB is a tightly closed barrier that protects the brain from harmful substances in circulation. It is still an unsolved question how metastatic cancer cells can invade through the protective barrier. In this project, we identify the factor that metastatic breast cancer secretes and investigate the effect of the factor on brain endothelial cells.

KIF13B-derived peptide and method of inhibiting angiogenesis (US 16/325,006, no. PCT/US2017/049584) published as WO 2018/045155 on March 8, 2018.